Collapse of the hepatic gene regulatory network in the absence of FoxA factors
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Abstract
The FoxA transcription factors are critical for liver development through their pioneering activity, which initiates a highly complex regulatory network thought to become progressively resistant to the loss of any individual hepatic transcription factor via mutual redundancy. To investigate the dispensability of FoxA factors for maintaining this regulatory network, we ablated all FoxA genes in the adult mouse liver. Remarkably, loss of FoxA caused rapid and massive reduction in the expression of critical liver genes. Activity of these genes was reduced back to the low levels of the fetal prehepatic endoderm stage, leading to necrosis and lethality within days. Mechanistically, we found FoxA proteins to be required for maintaining enhancer activity, chromatin accessibility, nucleosome positioning, and binding of HNF4α. Thus, the FoxA factors act continuously, guarding hepatic enhancer activity throughout adult life.
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In contrast to the Hnf4a cKO, there is no global effect on histone modifications between control and FTKO livers at HBRs.
“In contrast to the Hnf4a cKO, we observed no global effect on histone modifications between control and FTKO livers at HBRs (Supplementary Fig. 2b–d).”
From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [52]
The Results section on FoxA and enhancer activity reports substantial changes in histone marks at FoxA/HNF4α-cobound sites in triple-null livers, contrary to an unqualified claim of no effect at HNF4α-binding regions. Its analysis is limited to cobound sites and does not establish a global result across all HBRs; the paper also does not report the cited sentence’s histone-modification comparison with Hnf4a cKO. (LLM, conf=0.76)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredH3K4me1 and H3K27ac were also reduced in Hnf4a cKO liver at the extended set of HBRs identified by Reizel et al.
“While the Reizel dataset identified many additional HNF4A bound regions (over 36,000 total regions), we found H3K4me1 and H3K27ac were also reduced in Hnf4a cKO liver at this extended set of HBRs (Supplementary Fig. 1e).”
From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [52]
The Methods (ChIP-seq; page unavailable) confirm that Reizel et al. generated a dataset of HNF4α-binding regions, supporting its use as the identified set of HBRs. Our copy does not verify the stated total of over 36,000 regions. The reduction of H3K4me1 and H3K27ac in Hnf4a cKO liver is explicitly presented as the citing authors’ own finding, not as Reizel et al.’s result. (LLM, conf=0.81)
Experimental — accuracy not yet measuredHep-ID transcription factors comprise the well-accepted and thoroughly experimentally verified drivers of hepatocyte identity.
“Hep‐ID TFs comprise the well‐accepted and thoroughly experimentally verified drivers of hepatocyte identity (Reizel et al, 2020; Tachmatzidi et al, 2021).”
From An extended transcription factor regulatory network controls hepatocyte identity (2023) · cites this paper as Reizel et al, 2020
The Results section ('FoxA proteins maintain the activation state of a set of key liver genes'; page unavailable) reports that removing FoxA factors in adult mice reduces expression of key liver genes, experimentally supporting a role for FoxA in maintaining hepatocyte characteristics. The paper does not define a 'Hep-ID TF' group or verify that all factors in that group are drivers of hepatocyte identity, so it supports only the FoxA-specific part of the broader claim. (LLM, conf=0.84)
Experimental — accuracy not yet measured95% of our ~12,000 HBRs matched regions identified as bound by HNF4A in Reizel et al. data.
“we compared the adult mouse liver HNF4A ChIP-seq data from Reizel et al.52 to our HNF4A ChIP-seq data48,49 and observed that 95% of our ~12,000 HBRs matched regions identified as bound by HNF4A in their data (Supplementary Fig. 1d).”
From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [52]
FOXA factors are not always required for accessibility at HBRs.
“Furthermore, although FOXA factors act as pioneer factors in hepatocytes51,52, we show that FOXA factors are not always required for accessibility at HBRs.”
From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [52]
In mouse livers depleted for FOXAs, a subset of regions where HNF4A and FOXA normally co-bind lose HNF4A binding.
“Using mouse livers depleted for FOXAs, a subset of regions was identified where HNF4A and FOXA normally co-bound but HNF4A binding was also lost with loss of FOXAs52.”
From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [52]
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- Authors
- Reizel, Y., Morgan, A., Gao, L., Lan, Y., Manduchi, E., Waite, E. L., Wang, A. W., Wells, A., & Kaestner, K. H.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Kaestner, Klaus H.
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2020-06-19
- Volume
- 34
- Issue
- 15-16
- Pages
- 1039-1050
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC7397852
- OpenAlex
- W3035918211
- Cited by
- 60
- References
- 44
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 10 · 2023: 8 · 2022: 15 · 2021: 7 · 2020: 3
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Genes & Development (publishedVersion, cc-by-nc)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Pennsylvania Diabetes Research Center (P30 DK19525)
- Molecular Studies in Digestive and Liver Diseases (P30 DK050306)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- FoxA transcription factor, liver development, enhancer activity, chromatin accessibility, nucleosome positioning, HNF4α, liver necrosis, gene redundancy, liver-specific gene expression
- MeSH terms
- Animals, Binding Sites, Chromatin, Enhancer Elements, Genetic, Gene Expression Regulation, Liver, Male, Nucleosomes, Liver Failure, Mice, Hepatocyte Nuclear Factor 3-alpha, Hepatocyte Nuclear Factor 3-beta, Hepatocyte Nuclear Factor 3-gamma, Hepatocyte Nuclear Factor 4, Forkhead Transcription Factors, Gene Regulatory Networks, Gene Knockdown Techniques
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