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Cited by 7Liver physiology and pathologyHippo pathway signaling and YAP/TAZGenomics and Chromatin Dynamics

HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury

Open access
Yuan, Wei-Chien, Earl, Andrew S., Ma, Sai, Alcedo, Karel, Russell, Jacquelyn O., Duarte, Fabiana M., Chu, Yen-Ting, Chang, Pei-Chi +8 more·2025·Cell Stem Cell
DOI 10.1016/j.stem.2025.04.010PMC PMC12598758
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Abstract

Hepatocytes can reprogram into biliary epithelial cells (BECs) during liver injury, but the underlying epigenetic mechanisms remain poorly understood. Here, we define the chromatin dynamics of this process using single-cell ATAC-seq and identify YAP/TEAD activation as a key driver of chromatin remodeling. An in vivo CRISPR screen highlights the histone acetyltransferase HBO1 as a critical barrier to reprogramming. HBO1 is recruited by YAP to target loci, where it promotes histone H3 lysine 14 acetylation (H3K14ac) and engages the chromatin reader zinc-finger MYND-type containing 8 (ZMYND8) to suppress YAP/TEAD-driven transcription. Loss of HBO1 accelerates chromatin remodeling, enhances YAP binding, and enables a more complete hepatocyte-to-BEC transition. Our findings position HBO1 as an epigenetic brake that restrains YAP-mediated reprogramming, suggesting that targeting HBO1 may enhance hepatocyte plasticity for liver regeneration.

AI snapshot

Written from the paper’s full text.

TL;DR

HBO1 acts as an epigenetic brake on YAP/TEAD-driven hepatocyte-to-biliary reprogramming during liver injury. YAP recruits HBO1 to target loci, where HBO1 deposits H3K14ac and engages ZMYND8 to suppress YAP/TEAD transcription; HBO1 loss accelerates chromatin remodeling and enables a more complete transition.

Key findings

  • scATAC-seq in DDC and YAP-driven models showed reprogrammed hepatocytes acquire BEC-like but incomplete chromatin accessibility; TEAD motifs were enriched, and YAP activation caused rapid chromatin changes by day 3 followed by gradual transition to BECs by day 28, with BEC-specific changes emerging before loss of hepatocyte accessibility.
  • An in vivo CRISPR screen identified 13 other positive regulators and 8 negative regulators of YAP-driven reprogramming; five of five sgRNAs targeting Hbo1 were over-represented. HBO1 depletion increased hepatomegaly, clonal overgrowth, SOX9/CK19 expression, and accelerated YAP-mediated reprogramming, while HBO1 overexpression suppressed YAP-driven liver overgrowth and BEC reprogramming.
  • HBO1 depletion abolished H3K14ac with marginal effect on H4K12ac; the catalytic-dead HBO1 E508Q mutant acted dominantly negative and potentiated YAP-driven phenotypes. YAP expression increased HBO1 occupancy at YAP-bound regions, and >75% of YAP binding sites overlapped HBO1-bound regions; HBO1 loss increased YAP and TEAD4 occupancy and YAP target gene expression.
  • ZMYND8 was identified as a negative regulator; HBO1-driven inhibition of hepatomegaly after YAP activation was rescued by Zmynd8 loss, and Zmynd8 depletion increased H3K4me3 and YAP occupancy at target genes. In DDC injury, Hbo1 depletion caused a near 5-fold increase in hepatocyte-derived SOX9- or OPN-expressing cells; in MDA injury, HBO1 loss increased liver size and SOX9/OPN-expressing hepatocyte-lineage cells.

Methods

  • Mouse models included 0.1% DDC diet for 6 weeks, MDA at 50 mg/kg four times every other day, TetO-YAP-S127A and Cre-dependent Cas9 alleles, AAV2/8-Cre lineage tracing, and single-cell ATAC-seq (sciATAC/dscATAC) across reprogramming time points from day 0 to day 28.
  • The in vivo CRISPR screen used a Sleeping Beauty–integrated sgRNA library targeting epigenetic regulators, hydrodynamic tail-vein delivery, delayed tamoxifen, 6 weeks of doxycycline, sorting of EGFP+EPCAM+ cells, sgRNA sequencing, and STARS enrichment analysis.
  • Bulk ATAC-seq, RNA-seq, ChIP-seq/ChIP-qPCR, co-immunoprecipitation, immunohistochemistry/immunofluorescence, and RNA FISH were analyzed with chromVAR, cisTopic, UMAP, Louvain clustering, GSEA, DESeq2, CUT&RUNTools, and deepTools.

Limitations

  • Stated: further research is needed to translate these findings into clinically viable approaches, including development and use of small-molecule HBO1 inhibitors; findings are primarily based on murine models, so whether therapeutic HBO1 inactivation applies clinically remains to be determined.
  • Evident: the in vivo screen used an intermediate-size library; the authors note that larger and more complex libraries (up to 10-fold) could be screened and that improved library design would allow more complex screens. No human validation is presented in the paper.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.stem.2025.04.010

Cites

72 of 72 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

33 of 38 cited sources checked · 14 supported · 0 flagged · accuracy not yet measured

  • Interpretationown data

    Increased chromatin accessibility near YAP target genes suggests a pivotal role for YAP/TEAD signaling in the reprogramming process.

    “Furthermore, increased chromatin accessibility near YAP target genes suggested a pivotal role for YAP/TEAD signaling in the reprogramming process (Figure S1C), supporting previous data10.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] Yimlamai D, Christodoulou C, Galli GG, Yanger K, Pepe-Mooney B, Gurung B, Shrestha K, Cahan P, Stanger BZ, and Camargo FD (2014). Hippo pathway activity influences liver cell fate. Cell 157, 1324– 1338. 10.1016/j.cell.2014.03.060. 24906150 PMC4136468 source

      The Results sections on the liver progenitor program and NOTCH signaling support a role for YAP/TEAD in hepatocyte reprogramming: they report YAP-driven fate changes and YAP/TEAD binding and regulation of NOTCH-pathway genes. The paper reports chromatin occupancy, not increased chromatin accessibility near YAP target genes, so it does not support the specific observation used in the citing sentence. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Findingown data

    Even at day 28, reprogrammed hepatocytes maintained distinct chromatin accessibility compared to BECs, despite resembling them morphologically and transcriptionally.

    “Even at this later stage, reprogrammed hepatocytes maintained distinct chromatin accessibility compared to BECs (Figure 1H), despite resembling them morphologically and transcriptionally10 (Figure S1E).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [10] Yimlamai D, Christodoulou C, Galli GG, Yanger K, Pepe-Mooney B, Gurung B, Shrestha K, Cahan P, Stanger BZ, and Camargo FD (2014). Hippo pathway activity influences liver cell fate. Cell 157, 1324– 1338. 10.1016/j.cell.2014.03.060. 24906150 PMC4136468 source
  • Premisecitation

    ZMYND8 functions as a reader to recognize the acetylation of histone 3 at K14.

    “ZMYND8 (also named PRKCBP1 or RACK7) functions as a reader to recognize the acetylation of histone 3 at K14.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [35] Gong F, and Miller KM (2018). Double duty: ZMYND8 in the DNA damage response and cancer. Cell Cycle 17, 414– 420. 10.1080/15384101.2017.1376150. 29393731 PMC5927707 source
    • cites [36] Li N, Li Y, Lv J, Zheng X, Wen H, Shen H, Zhu G, Chen TY, Dhar SS, Kan PY, (2016). ZMYND8 Reads the Dual Histone Mark H3K4me1-H3K14ac to Antagonize the Expression of Metastasis-Linked Genes. Mol Cell 63, 470– 484. 10.1016/j.molcel.2016.06.035. 27477906 PMC4975651 source
    • cites [37] Shen H, Xu W, Guo R, Rong B, Gu L, Wang Z, He C, Zheng L, Hu X, Hu Z, (2016). Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex. Cell 165, 331– 342. 10.1016/j.cell.2016.02.064. 27058665 PMC4826479 source

      The Results section ('RACK7 primarily binds active enhancers'; page unavailable) identifies RACK7 as ZMYND8 and reports its binding at active enhancers. It describes the related protein BS69/ZMYND11—not RACK7—as a histone-mark reader. Searches for H3K14, lysine-14 acetylation, and acetylated-histone recognition found no passage saying that ZMYND8 reads H3K14 acetylation. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Findingown data

    Single molecule FISH measurements for Amotl2 demonstrated increased expression of this transcript in Hbo1-depleted hepatocytes.

    “Notably, single molecule FISH measurements for Amotl231, a well-known YAP target, demonstrated the increased expression of this transcript in Hbo1-depleted hepatocytes (Figure 4C).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [31] Yu FX, Zhao B, and Guan KL (2015). Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. Cell 163, 811– 828. 10.1016/j.cell.2015.10.044. 26544935 PMC4638384 source

      The cited review does not report single-molecule FISH measurements or increased Amotl2 expression in Hbo1-depleted hepatocytes; the citing sentence points to its own Figure 4C for that result. The review’s “Hippo Pathway in Early Embryonic Development” section mentions AMOT/AMOTL2 depletion in embryos, but does not address this measurement. Searches for Amotl2 and Hbo1-depleted hepatocytes found no supporting passage. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Premisecitation

    Similar observations in humans suggest that hepatocyte-to-BEC conversion may play a role in conditions such as biliary obstruction and primary biliary cirrhosis.

    “and similar observations in humans suggest that hepatocyte-to-BEC conversion may play a role in conditions such as biliary obstruction and primary biliary cirrhosis49.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [49] Limaye PB, Alarcon G, Walls AL, Nalesnik MA, Michalopoulos GK, Demetris AJ, and Ochoa ER (2008). Expression of specific hepatocyte and cholangiocyte transcription factors in human liver disease and embryonic development. Lab Invest 88, 865– 872. 10.1038/labinvest.2008.56. 18574450 PMC2631390 source
  • Classified as probably not a substantial claim. 25
  • May combine two claims. 31

  • Classified as probably not a substantial claim.

    Premisecitation

    Acute YAP overexpression results in hepatocyte reprogramming into BEC.

    “Acute YAP overexpression results in hepatocyte reprogramming into BEC10.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [10] Yimlamai D, Christodoulou C, Galli GG, Yanger K, Pepe-Mooney B, Gurung B, Shrestha K, Cahan P, Stanger BZ, and Camargo FD (2014). Hippo pathway activity influences liver cell fate. Cell 157, 1324– 1338. 10.1016/j.cell.2014.03.060. 24906150 PMC4136468 source

      In Results, under “YAP activation de-differentiates single adult hepatocytes” (page unavailable), lineage tracing shows that YAP induction gives hepatocytes ductal markers and a ductal/progenitor-like fate. The paper does not establish that acute overexpression converts them into mature biliary epithelial cells: many cells at one week retained a hepatocyte marker, and the reported fate change progressed over weeks. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    YAP predominantly exerts its transcriptional functions through interaction with the TEAD family of transcription factors.

    “YAP predominantly exerts its transcriptional functions through interaction with the TEAD family of transcription factors, thereby promoting the expression of target genes12,13.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [12] Wu S, Liu Y, Zheng Y, Dong J, and Pan D. (2008). The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway. Developmental cell 14, 388– 398. 10.1016/j.devcel.2008.01.007. 18258486 source

      The Introduction reports that YAP interacts with TEAD/TEF transcription factors, and the Discussion suggests that the growth-regulatory activity of the fly Sd–Yki complex is conserved in mammals. The paper does not establish that YAP uses TEAD for *most* of its transcriptional functions; it also names other YAP-interacting transcription factors. Page numbers are unavailable in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [13] Zhang L, Ren F, Zhang Q, Chen Y, Wang B, and Jiang J. (2008). The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control. Developmental cell 14, 377– 387. 10.1016/j.devcel.2008.01.006. 18258485 PMC2292673 source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    YAP is necessary and sufficient for hepatocyte reprogramming into ductal cells.

    “YAP, the main transducer of the Hippo pathway, has been reported to be necessary and sufficient for hepatocyte reprogramming into ductal cells10,11.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [10] Yimlamai D, Christodoulou C, Galli GG, Yanger K, Pepe-Mooney B, Gurung B, Shrestha K, Cahan P, Stanger BZ, and Camargo FD (2014). Hippo pathway activity influences liver cell fate. Cell 157, 1324– 1338. 10.1016/j.cell.2014.03.060. 24906150 PMC4136468 source

      The Results section, “YAP activation de-differentiates single adult hepatocytes” (page unavailable), explicitly says high YAP levels are sufficient to impose a ductal/progenitor-like fate on adult hepatocytes. The passages found do not establish that YAP is necessary for hepatocyte-to-ductal reprogramming; the loss-of-function result in “NOTCH signaling downstream of YAP during reprogramming” concerns NOTCH signaling, not YAP. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [11] Monroe TO, Hill MC, Morikawa Y, Leach JP, Heallen T, Cao S, Krijger PHL, de Laat W, Wehrens XHT, Rodney GG, and Martin JF (2019). YAP Partially Reprograms Chromatin Accessibility to Directly Induce Adult Cardiogenesis In Vivo. Developmental cell 48, 765– 779 e767. 10.1016/j.devcel.2019.01.017. 30773489 PMC6435425 source

      The Introduction identifies YAP as a Hippo-pathway effector, supporting that background part of the sentence. The Discussion section on YAP, ploidy and cell-cycle progression mentions hepatocyte proliferation, but neither it nor the other passages found addresses whether YAP is necessary and sufficient to reprogram hepatocytes into ductal cells. No page numbers were available in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Loss of Nf2 or Lats1/2 forces hepatocytes to commit to the BEC lineage.

    “Additionally, loss of Nf2 or Lats1/2 forces hepatocytes to commit to the BEC lineage14,15.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [14] Lee DH, Park JO, Kim TS, Kim SK, Kim TH, Kim MC, Park GS, Kim JH, Kuninaka S, Olson EN, (2016). LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development. Nature communications 7, 11961. 10.1038/ncomms11961. PMC4931324 27358050 source

      The Results section, “Lats1/2 deletion triggers transition of hepatocytes to BECs” (page unavailable), reports that roughly 60% of immature BECs arose from Lats1/2-deficient hepatocytes via de-differentiation. This supports the Lats1/2 part, although “forces hepatocytes” is broader than the reported finding. The Methods mention Nf2 mice, but the passages found do not show that Nf2 loss causes this transition. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [15] Zhang N., Bai H., David KK., Dong J., Zheng Y., Cai J., Giovsnnini M., Liu P., Anders RA., and Pan D. (2010). The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Developmental cell 19, 27– 38. 10.1016/j.devcel.2010.06.015. 20643348 PMC2925178 source

      The Results section, “Loss of NF2 leads to hepatocyte and biliary epithelium overproliferation” (page unavailable), reports excess BECs after Nf2 deletion, but describes the proliferating cells as being of biliary origin; it does not show hepatocytes committing to the BEC lineage. The Results section, “NF2 is required for Hippo signaling” (page unavailable), reports reduced Lats1/2 activity in Nf2-deficient livers, not the effect of deleting Lats1/2. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    ZMYND8 occupies many active enhancers and recruits KDM5C to super enhancer regions to maintain low H3K4me3 levels resulting in repression of enhancer activity.

    “ZMYND8 occupies many active enhancers and recruits KDM5C to super enhancer regions to maintain low H3K4me3 levels resulting in the repression of enhancer activity 35–37.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [35] Gong F, and Miller KM (2018). Double duty: ZMYND8 in the DNA damage response and cancer. Cell Cycle 17, 414– 420. 10.1080/15384101.2017.1376150. 29393731 PMC5927707 source
    • cites [36] Li N, Li Y, Lv J, Zheng X, Wen H, Shen H, Zhu G, Chen TY, Dhar SS, Kan PY, (2016). ZMYND8 Reads the Dual Histone Mark H3K4me1-H3K14ac to Antagonize the Expression of Metastasis-Linked Genes. Mol Cell 63, 470– 484. 10.1016/j.molcel.2016.06.035. 27477906 PMC4975651 source

      The Results (page unavailable) show that ZMYND8 and JARID1D cooperate to repress metastasis-linked genes: ZMYND8 knockdown reduced JARID1D occupancy and increased H3K4me3 at those genes. The Discussion (page unavailable) suggests ZMYND8 may help recruit JARID1D. These passages do not establish recruitment of KDM5C to super-enhancer regions or repression of enhancer activity. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [37] Shen H, Xu W, Guo R, Rong B, Gu L, Wang Z, He C, Zheng L, Hu X, Hu Z, (2016). Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex. Cell 165, 331– 342. 10.1016/j.cell.2016.02.064. 27058665 PMC4826479 source

  • May combine two claims.

    Findingown data

    GSEA showed that upon YAP expression, HBO1-depletion induced significant positive enrichment of a BEC signature and negative enrichment of a hepatocyte signature.

    “Moreover, GSEA analysis showed that upon YAP expression, HBO1-depletion induced significant positive enrichment of a BEC signature16 and negative enrichment of a hepatocyte signature (Figure S5J).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] Pepe-Mooney BJ, Dill MT, Alemany A, Ordovas-Montanes J, Matsushita Y, Rao A, Sen A, Miyazaki M, Anakk S, Dawson PA, (2019). Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration. Cell Stem Cell 25, 23– 38 e28. 10.1016/j.stem.2019.04.004. 31080134 PMC6814390 source

  • May combine two claims.

    Findingown data

    Single cell molecule FISH of YAP target genes Cyr61 and Amotl2 validated their dramatically higher expression in vivo in the absence of HBO1 and their attenuation following HBO1 overexpression.

    “Single cell molecule FISH of YAP target genes, Cyr61 and Amotl231, validated their dramatically higher expression in vivo in the absence of HBO1 (Figure 5F, 5G and S5G, and their attenuation following HBO1 overexpression (Figure S5H).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [31] Yu FX, Zhao B, and Guan KL (2015). Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. Cell 163, 811– 828. 10.1016/j.cell.2015.10.044. 26544935 PMC4638384 source

      The citation is attached to the identification of Cyr61 and Amotl2 as YAP target genes, not to the citing authors’ FISH results. The review’s ‘YAP/TAZ and Yki as Major Effectors of Hippo Signaling’ section discusses YAP target genes generally but does not identify Cyr61 or Amotl2 as targets. Searches for those genes and HBO1 found no passage supporting the specific claim; the review mentions AMOTL2 in a different context, as a Hippo-pathway component. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Published ChIP-seq datasets reveal a similar phenomenon in human cancer cell lines.

    “Consistently, published ChIP-seq datasets34,38,39 reveal a similar phenomenon in human cancer cell lines (Figure S7F).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [34] Galli GG, Carrara M, Yuan WC, Valdes-Quezada C, Gurung B, Pepe-Mooney B, Zhang T, Geeven G, Gray NS, de Laat W, (2015). YAP Drives Growth by Controlling Transcriptional Pause Release from Dynamic Enhancers. Mol Cell 60, 328– 337. 10.1016/j.molcel.2015.09.001. 26439301 PMC4624327 source
    • cites [38] Stein C, Bardet AF, Roma G, Bergling S, Clay I, Ruchti A, Agarinis C, Schmelzle T, Bouwmeester T, Schubeler D, and Bauer A. (2015). YAP1 Exerts Its Transcriptional Control via TEAD-Mediated Activation of Enhancers. PLoS Genet 11, e1005465. 10.1371/journal.pgen.1005465. 26295846 PMC4546604 source
    • cites [39] Zanconato F, Forcato M, Battilana G, Azzolin L, Quaranta E, Bodega B, Rosato A, Bicciato S, Cordenonsi M, and Piccolo S. (2015). Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat Cell Biol 17, 1218– 1227. 10.1038/ncb3216. 26258633 PMC6186417 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    For the histone mark H3K14ac, the recommended histone ChIP-seq normalization pipeline was used to generate scale factors.

    “For the histone mark H3K14ac, we used the recommended histone ChIP-seq normalization pipeline64 to generate scale factors.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [64] Jin H, Kasper LH, Larson JD, Wu G, Baker SJ, Zhang J, and Fan Y. (2020). ChIPseqSpikeInFree: a ChIP-seq normalization approach to reveal global changes in histone modifications without spike-in. Bioinformatics (Oxford, England) 36, 1270– 1272. 10.1093/bioinformatics/btz720. 31566663 PMC7523640 source

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    TAM delivery was delayed by 3 weeks post-hydrodynamic injection until loss of episomal plasmids occurred.

    “In order to ensure that sgRNA-mediated knockout only occurred in hepatocytes carrying an integrated plasmid cassette, TAM delivery was delayed by 3 weeks post-hydrodynamic injection until loss of episomal plasmids occurred25.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [25] Bell JB, Aronovich EL, Schreifels JM, Beadnell TC, and Hackett PB (2010). Duration of expression and activity of Sleeping Beauty transposase in mouse liver following hydrodynamic DNA delivery. Mol Ther 18, 1796– 1802. 10.1038/mt.2010.152. 20628359 PMC2951564 source

      The section on SB transposase gene loss reports that plasmid copy number fell by 90% over the first two weeks after hydrodynamic delivery, supporting a substantial decline by three weeks. It also says the remaining 10% stabilized, so the paper does not establish complete loss of episomal plasmids or that waiting three weeks ensures activity only in hepatocytes with an integrated cassette. The paper does not study TAM delivery. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Under physiological conditions, activation of YAP is necessary and sufficient to reprogram hepatocytes and to precisely control developmental outcomes, organ size and tissue repair.

    “Under physiological conditions, activation of YAP is necessary and sufficient to not only reprogram hepatocytes but to precisely control developmental outcomes, organ size and tissue repair10,16,40,41.”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [10] Yimlamai D, Christodoulou C, Galli GG, Yanger K, Pepe-Mooney B, Gurung B, Shrestha K, Cahan P, Stanger BZ, and Camargo FD (2014). Hippo pathway activity influences liver cell fate. Cell 157, 1324– 1338. 10.1016/j.cell.2014.03.060. 24906150 PMC4136468 source

      The Results section, “YAP activation de-differentiates single adult hepatocytes” (page not supplied), reports that high levels of YAP are sufficient to impose a progenitor-like fate on adult hepatocytes. It does not establish that YAP activation is necessary for reprogramming under physiological conditions. The Discussion (page not supplied) describes a possible role in liver repair, rather than demonstrating precise control of developmental outcomes, organ size, and tissue repair. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [16] Pepe-Mooney BJ, Dill MT, Alemany A, Ordovas-Montanes J, Matsushita Y, Rao A, Sen A, Miyazaki M, Anakk S, Dawson PA, (2019). Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration. Cell Stem Cell 25, 23– 38 e28. 10.1016/j.stem.2019.04.004. 31080134 PMC6814390 source

      The Results section ('YAP is Essential in Hepatocytes for the Regenerative Ductular Response to Injury'; page not provided) shows that deleting YAP impairs hepatocyte reprogramming and the regenerative response after DDC injury. The Discussion reports that overexpression of active YAP drives reprogramming, citing earlier work. This does not establish necessity and sufficiency under physiological conditions, or precise control of developmental outcomes and organ size; the Results also report no detectable high-YAP signature in homeostatic hepatocytes. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [40] Moya IM, and Halder G. (2019). Hippo-YAP/TAZ signalling in organ regeneration and regenerative medicine. Nature reviews. Molecular cell biology 20, 211– 226. 10.1038/s41580-018-0086-y. 30546055 source

      The sections ‘YAP promotes dedifferentiation and stemness’ and ‘YAP activation and liver regeneration’ report that experimental YAP overexpression reprogrammed mouse hepatocytes into progenitor-like cells and enhanced liver repair. They do not establish that YAP activation is necessary for hepatocyte reprogramming under physiological conditions. The sections on growth and regeneration describe tissue-specific effects, not precise control of developmental outcomes, organ size and repair; liver regeneration was delayed, but not prevented, when Yap and Taz were deleted. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [41] Varelas X. (2014). The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease. Development (Cambridge, England) 141, 1614– 1626. 10.1242/dev.102376. 24715453 source

  • May combine two claims.

    Findingown data

    scATAC-seq analysis unveiled major differences in chromatin landscape between hepatocytes and BECs, whereas DDC-induced reprogrammed hepatocytes exhibited overlapping chromatin accessibility with BECs.

    “scATAC-seq analysis unveiled major differences in chromatin landscape between hepatocytes and BECs, whereas DDC-induced reprogrammed hepatocytes exhibited overlapping chromatin accessibility with BECs (Figure 1B and 1C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Quantifying reprogramming using hepatic and biliary ID scores indicated a gradual transition from clusters 1 to cluster 4, with reprogrammed cells showing intermediate scores.

    “Quantifying reprogramming using hepatic and biliary ID scores (see Methods) indicated a gradual transition from clusters 1 to cluster 4, with reprogrammed cells showing intermediate scores (Figure 1D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the presence of Dox for two weeks, Hbo1 depletion promoted earlier SOX9 and panCK expression, indicating that Hbo1 depletion accelerates YAP-mediated reprogramming.

    “In the presence of Dox for two weeks, Hbo1 depletion promoted earlier SOX9 and panCK expression, indicating that Hbo1 depletion accelerates YAP-mediated reprogramming (Figure 3E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Depletion of HBO1 in hepatocytes significantly reduced H3K14 acetylation and increased liver size in the MDA model.

    “Compared with control, depletion of HBO1 in hepatocytes significantly reduced the level of H3K14 acetylation (Figure S4C) and increased the liver size (Figure 4D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Loss of HBO1 specifically in hepatocytes resulted in loss of H3K14 acetylation and significant augmentation of the ductular reaction post-DDC as measured by increased panCK positive cells.

    “Compared with control, loss of HBO1 specifically in hepatocytes resulted in a loss of H3K14 acetylation (Figure S4A) and led to significant augmentation of the ductular reaction post-DDC as measured by increased panCK positive cells (Figure 4A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Compared with control, YAP-induced chromatin accessibility changes proceeded with faster dynamics in the context of HBO1 depletion, including gain of chromatin accessibility in biliary specific genes, YAP target genes and cell cycle related genes, while concurrently loss of chromatin accessibility of hepatic genes.

    “Again, compared with control, YAP-induced chromatin accessibility changes proceeded with faster dynamics in the context of HBO1 depletion, including gain of chromatin accessibility in biliary specific genes, YAP target genes and cell cycle related genes, while concurrently loss of chromatin accessibility of hepatic genes (Figure 5H and 5I).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Overexpression of Hbo1 led to near complete suppression of YAP-driven liver overgrowth, decreased hepatocyte proliferation, and diminished BEC reprogramming.

    “Conversely, overexpression of Hbo1 using a transposon construct led to a near complete suppression of YAP-driven liver overgrowth (Figure 3F and 3G), decreased hepatocyte proliferation, and diminished BEC reprogramming (Figure 3H, 3I, S3B, S3C, S3D and S3E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ChIP-qPCR studies demonstrate that Zmynd8 depletion significantly increases the levels of H3K4me3 and the occupancy of YAP at target genes.

    “Furthermore, ChIP-qPCR studies demonstrate that Zmynd8 depletion significantly increases the levels of H3K4me3 and the occupancy of YAP at target genes (Figure 7E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HBO1 depletion enhanced and accelerated accessibility of YAP target genes and BEC specific genes during reprogramming.

    “Notably, examination of the chromatin landscape in a number of representative regions revealed that HBO1 depletion enhanced and accelerated accessibility of YAP target genes (Figure 5B and S5E) and BEC specific genes (Figure 5C) during reprogramming.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Individual transposon sgRNA-mediated knockout of Hbo1 in combination with YAP overexpression led to major hepatomegaly phenotypes and clonal overgrowth.

    “Individual transposon sgRNA-mediated knockout of Hbo1 in combination with YAP overexpression led to major hepatomegaly phenotypes (Figure 3A and B) and clonal overgrowth (Figure 2I).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Analysis revealed rapid chromatin changes by day 3 post-YAP activation, followed by a gradual transition to BECs by day 28.

    “Our analysis revealed rapid chromatin changes by day 3 post-YAP activation, followed by a gradual transition to BECs by day 28.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Hbo1 knockout clones exhibited increased proliferative indices and biliary molecular features indicated by expression of SOX9 and CK19.

    “Hbo1 knockout clones exhibited increased proliferative indices and biliary molecular features indicated by the expression of SOX9 and CK19 (early and late reprogramming markers, respectively) (Figure 3C and Figure S3A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HBO1 depletion dramatically abolished H3K14ac but displayed marginal effect on H4K12ac in liver samples and in a cholangiocarcinoma cell line.

    “We found that HBO1 depletion dramatically abolished H3K14ac but displayed marginal effect on H4K12ac in liver samples and in a cholangiocarcinoma cell lines (Figure 3J, S3F and S3G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Global transcriptome analysis revealed that HBO1 depletion only displayed some hepatocyte and BEC identity genes changes with no significant trends toward any cell fate transitions.

    “Global transcriptome analysis revealed that HBO1 depletion only displayed some hepatocyte and BEC identity genes changes with no significant trends toward any cell fate transitions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The screen hits include histone acetyltransferases Tip60, Mof, Moz and Hbo1, lysine methyltransferases Setd1b, Setdb1, Setd8, Dot1l, Ehmt1 and Ehmt2, lysine demethylases Kdm6a and Phf8, histone deacetylase Sirt1, and bromodomain-containing proteins Brd1 and Zmynd8.

    “Our hits include histone acetyltransferases (Tip60, Mof, Moz and Hbo1), lysine methyltransferases (Setd1b, Setdb1, Setd8, Dot1l, Ehmt1 and Ehmt2), lysine demethylases (Kdm6a, and Phf8), histone deacetylases (Sirt1), and bromodomain-containing proteins (Brd1 and Zmynd8).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aggregated scATAC-seq track data confirmed opening of chromatin at regulatory regions of BEC-specific genes, while minimal changes were noted in regulatory regions surrounding hepatocyte-specific genes even 28 days after YAP induction.

    “Aggregated scATAC-seq track data confirmed the opening of chromatin at regulatory regions of BEC-specific genes, while minimal changes were noted in regulatory regions surrounding hepatocyte-specific genes, even 28 days after YAP induction (Figure 1J)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Global analysis of TF motifs showed more rapid and profound changes in chromatin accessibility upon HBO1 depletion, leading to an epigenetic state that more closely resembles bona fide BECs.

    “This accelerated and enhanced reprogramming was corroborated by the global analysis of TF motifs, where we again observed more rapid and profound changes in chromatin accessibility (Figure 5E), leading to an epigenetic state that more closely resembles bona fide BECs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Enrichment of JUN/FOS, NFκB and BACH2 transcription factor motifs strongly increased as cells reprogram, while binding motifs of LEF1/TCF7L2 factors related to Wnt signaling displayed reduced accessibility.

    “For instance, enrichment of motifs of JUN/FOS, NFκB and BACH2 transcription factor are strongly increased as cells reprogram, while the binding motifs of LEF1/TCF7L2 factors related to Wnt signaling display reduced accessibility (Figure 1F).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    YAP-mediated HBO1 induction and recruitment form a negative feedback loop to self-regulate its own transcriptional outputs and control the hepatocyte-to-BEC fate transition.

    “Together with our previous results, these data speak to a model where YAP-mediated HBO1 induction and recruitment form a negative feedback loop to self-regulate its own transcriptional outputs and control the hepatocyte-to-BEC fate transition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    HBO1 participates in YAP-driven reprogramming and regeneration through the alteration of both chromatin landscape and transcriptome.

    “Collectively, these data indicate that HBO1 participates in YAP-driven reprogramming and regeneration through the alteration of both chromatin landscape and transcriptome.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    HBO1 functions as an epigenetic 'brake' for YAP functions and hepatocyte reprogramming.

    “In this context, we posit HBO1 functions as an epigenetic ‘brake’ for YAP functions and hepatocyte reprogramming (Figure 7F).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The number of PCR cycles was optimized by DNA quantification to stop in the middle of the linear amplification phase.

    “The number of cycles was optimized by DNA quantification to stop in the middle of the linear amplification phase.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    Since the findings are primarily based on murine models, it remains to be determined whether therapeutic inactivation of HBO1 can be successfully applied in clinical settings.

    “Additionally, since our findings are primarily based on murine models, it remains to be determined whether the therapeutic inactivation of HBO1 can be successfully applied in clinical settings.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Transcription factors YAP, TEAD4, and HBO1 were normalized using equal background normalization.

    “Transcription factors YAP, TEAD4, HBO1 adopted equal background normalization.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The average of technical replicates was used to represent the value of each biological replicate.

    “The average of technical replicates was used to represent the value of each biological replicate.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    YAP-mediated HBO1 induction and recruitment promote acetylation of H3 at K14 and engage ZMYND8 to restrict its own transcriptional output.

    “Here, we elucidate mechanisms by which YAP-mediated HBO1 induction and recruitment promote the acetylation of H3 at K14 and engage ZMYND8 to restrict its own transcriptional output.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Normalizing ChIP-seq samples according to the described procedure enables comparison between Dox(−) and Dox(+) samples.

    “To enable a comparison between Dox (−) and Dox (+) samples, we normalized the samples according to the following procedure.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Approximately 70-95% of high quality reads contained the sgRNA scaffold inside the amplified region.

    “Approximately 70–95% of high quality reads contained the sgRNA scaffold inside the amplified region and were extracted from the raw fasta files using grep (sgRNA specific reads).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Statistical analysis was performed on biological replicates to compare control and treatment groups.

    “Statistical analysis was performed on biological replicates to compare control and treatment groups.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    At least 2000-fold colonies per sgRNA clone were recovered in each transformation to preserve the diversity of the sgRNA library.

    “To preserve the diversity of the library, at least 2000-fold colonies per sgRNA clone were recovered in each transformation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Reads were mapped allowing 1 mismatch, and sequences that mapped to more than 1 single site were discarded.

    “We allowed 1 mismatch, and discarded any sequences that mapped to more than 1 single site.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Any preps with cross contamination larger than 1% of the total mappable reads were excluded.

    “We excluded any preps with cross contamination larger than 1% of the total mappable reads.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    It is likely that HBO1 and ZMYND8 will play important roles in other facets of liver biology and disease.

    “Considering the multiple roles that YAP plays in the liver, it is likely that HBO1 and ZMYND8 will play important roles in other facets of liver biology and disease.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    The dose of plasmids delivered was titrated to achieve an average integration frequency of one transposon per cell, thereby resulting in a single gene knockout per hepatocyte.

    “Moreover, the dose of plasmids delivered was titrated to achieve an average integration frequency of one transposon per cell, thereby resulting in a single gene knockout per hepatocyte (Figure S2C).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Each transcription factor or histone factor was normalized separately from the others.

    “Each TF or histone factor was normalized separately from others.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    For statistical analysis of image quantification results, each lane represents a different biological replicate, and each dot within the lanes indicates measurement values from technical replicates.

    “For statistical analysis of image quantification results, each lane represents a different biological replicate, while each dot within the lanes indicates measurement values from technical replicates.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    There was little to no change in the representation of scramble sgRNAs, whereas sgRNAs targeting the human YAP transgene were collectively the most underrepresented sequences, validating the screening approach.

    “As expected, there was little to no change in the representation of scramble sgRNAs, whereas sgRNAs targeting the human YAP transgene were, collectively, the most underrepresented sequences, validating our screening approach (Figure 2F and 2G).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    For comparing scATAC and bulk ATAC datasets, peaks defined by scATAC data were used.

    “For comparing scATAC and bulk ATAC datasets, peaks defined by scATAC data were used.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    Our data suggest that much larger and complex libraries (up to 10-fold) could be screened.

    “Although our experiments described here utilize an intermediate size library, our data suggest that much larger and complex libraries (up to 10-fold) could be screened.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Inter-sample contamination was assessed and excluded by measuring sgRNA reads corresponding to distinct sgRNA pools within the same sequencing sample.

    “As an additional quality control, inter-sample contamination was assessed and excluded by measuring sgRNA reads corresponding to distinct sgRNA pools within the same sequencing sample.”
    Quote in the paperNot a substantial claim
51 of 51

  • The paper relies on this without support.

    A major gap exists in knowledge of the nature of the epigenetic changes that occur during hepatocyte reprogramming.

    “However, a major gap in our knowledge is the nature of the epigenetic changes that occur during this reprogramming journey.”

  • The paper relies on this without support.

    The identity of epigenetic regulators underlying the hepatocyte-to-BEC cell fate transition is elusive.

    “Additionally, the identity of epigenetic regulators underlying this cell fate transition is elusive.”

  • The paper relies on this without support.

    EPCAM is a late stage biliary reprogramming marker.

    “We isolated hepatocyte-derived reprogrammed cells through EPCAM (a late stage biliary reprogramming marker) and TOM expression (Figure S1A)”
3 of 3

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • DDC is given two different chemical names

    Minor

    The same DDC treatment is identified as dihydrocollidine in the Results and dihydroxychollidine in the Methods. These are different chemical names, so the identity of the administered compound is inconsistent.

  • Newly generated plasmid conflicts with materials-availability statement

    Minor

    The materials-availability statement says the study generated no new unique reagents, but the methods explicitly say the authors cloned SB100 into a vector to generate an AAV-virus expression plasmid.

2 of 2

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Authors
Yuan, W.-C., Earl, A. S., Ma, S., Alcedo, K., Russell, J. O., Duarte, F. M., Chu, Y.-T., Chang, P.-C., Chen, H.-Y., Chi, H.-H., Zhu, Q., Rodriguez-Fraticelli, A. E., Patel, S. H., Lee, Y.-R., Buenrostro, J. D., & Camargo, F. D.
Affiliations
  • Boston Children's Hospital (US)
  • Broad Institute (US)
  • National Yang Ming Chiao Tung University (TW)
  • Institute of Biomedical Sciences, Academia Sinica (TW)
  • Harvard University (US)
Corresponding author
  • Yuan, Wei-Chien
  • Camargo, Fernando D.
ORCID
Venue
Cell Stem Cell
Publisher
Elsevier BV
Published
2025-06
Volume
32
Issue
6
Pages
990-1005.e8
ISSN
  • 1875-9777 (ISSN-L)
  • 1934-5909
DOI
10.1016/j.stem.2025.04.010
PMC
PMC12598758
OpenAlex
W4410550728
Semantic Scholar
3930904f10d7e9f809c7a26103328a26b8d0a10a
Cited by
7
References
72
Citations by year
2026: 6 · 2025: 1
FWCI
3.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell stem cell (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • Academia Sinica (110-2320-B-001-029-MY2, 112-2628-B-001-010-MY3, AS-CDA-110-L07)
  • National Science and Technology Council (112-2628-B-A49-006, 111-2628-B-A49-019, 110-2628-B-A49A-515, 113-2311-B-A49-006-MY3, 113-2628-B-A49-006)
  • National Health Research Institutes (NHRI-EX114-11415BC)
  • National Institutes of Health (AR064036, DK099559, P30DK034854)
  • Harvard Digestive Diseases Center, Harvard University
  • National Yang Ming Chiao Tung University
  • National Cancer Center (AS-CFII112-204)
  • Ministry of Education (MOE-108-YSFMS-0004-012-P1, 112W31101, 113W031101, 114W031101)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
HBO1, liver injury, chromatin remodeling, H3K14 acetylation, ZMYND8, histone acetyltransferase, epigenetic regulation, liver regeneration, chromatin dynamics
MeSH terms
Cell Plasticity, YAP-Signaling Proteins, Acetylation, Animals, Histones, Humans, Liver, Liver Regeneration, Transcription Factors, Hepatocytes, Chromatin Assembly and Disassembly, Epigenesis, Genetic, Adaptor Proteins, Signal Transducing, Mice, Histone Acetyltransferases, Cellular Reprogramming

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-22.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-22.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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