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The Caenorhabditis elegans Ortholog of TDP-43 Regulates the Chromatin Localization of the Heterochromatin Protein 1 Homolog HPL-2

Saldi, Tassa K., Gonzales, Patrick, Garrido-Lecca, Alfonso, Dostal, Vishantie, Roberts, Christine M., Petrucelli, Leonard, Link, Christopher D.·2018·Molecular and Cellular Biology
DOI 10.1128/mcb.00668-17PMC PMC6048318
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FIG 1 TDP-1 limits the efficiency of exogenous RNAi. (A) Percentages of animals affected by treatment with RNAi against the indicated genes. (B) Suppression of neuron-specific unc-73 RNAi by transgenic pan-neuronal overexpression of TDP-1. (C) Representative pictures of GFP fluorescence in wild-type and tdp-1(ok803) animals expressing GFP driven by a myo-3 (muscle-specific) promoter that were treated with GFP feeding RNAi for 24 h. Treatment was done two independent times. (D) Western blots of total proteins from wild-type (WT) and tdp-1(ok803) GFP-expressing animals before and after 24 h of GFP RNAi (top two panels) or treatment with empty vector (bottom two panels). CPF-1 is a loading control. (E and F) Percentages of wild-type and tdp1(ok781) animals affected by RNAi of the indicated genes. (G) Representative images of wild-type and tdp-1(ok781) animals expressing GFP driven by a myo-3 (muscle-specific) promoter that were treated with GFP RNAi or empty vector for 24 h. For panels A, B, E, and F, RNAi assays were performed three independent times (in triplicate), with >100 animals scored per plate. P values across three biological replicates were calculated by Student's t test; error bars show standard errors of the means (SEM).
FIG 1 TDP-1 limits the efficiency of exogenous RNAi. (A) Percentages of animals affected by treatment with RNAi against the indicated genes. (B) Suppression of neuron-specific unc-73 RNAi by transgenic pan-neuronal overexpression of TDP-1. (C) Representative pictures of GFP fluorescence in wild-type and tdp-1(ok803) animals expressing GFP driven by a myo-3 (muscle-specific) promoter that were treated with GFP feeding RNAi for 24 h. Treatment was done two independent times. (D) Western blots of total proteins from wild-type (WT) and tdp-1(ok803) GFP-expressing animals before and after 24 h of GFP RNAi (top two panels) or treatment with empty vector (bottom two panels). CPF-1 is a loading control. (E and F) Percentages of wild-type and tdp1(ok781) animals affected by RNAi of the indicated genes. (G) Representative images of wild-type and tdp-1(ok781) animals expressing GFP driven by a myo-3 (muscle-specific) promoter that were treated with GFP RNAi or empty vector for 24 h. For panels A, B, E, and F, RNAi assays were performed three independent times (in triplicate), with >100 animals scored per plate. P values across three biological replicates were calculated by Student's t test; error bars show standard errors of the means (SEM).CC BY · PubMed Central
FIG 2 TDP-1 limits RNAi by limiting nuclear RNAi. (A) (Top) Representative examples of GFP fluorescence in the untreated progeny (L4) of GFP RNAi-treated parents expressing a myo-3::GFP transgene in wild-type and tdp-1(ok803) backgrounds. (Bottom) Western blots of total proteins from 48-h-old untreated progeny of wild-type and tdp-1(ok803) animals treated with GFP feeding RNAi or empty vector. CPF-1 is a loading control. (B) Percentages of animals affected by lir-1 feeding RNAi. A schematic of the operon containing lir-1 and lin-26 is shown at the top. Boxes indicate genes, and the line represents the intercistronic space. The P value was calculated by Student's t test. (C) Loss of NRDE-3 function reverses the enhanced RNAi efficiency of the tdp-1(ok803) mutant. Genes targeted by RNAi in the indicated strains are shown on the x axis. P values were calculated by comparing values for the tdp-1(ok803) mutant alone to those for the tdp-1(ok803); nrde-3(gg66) double mutant by Student's t test. In panels B and C, error bars show SEM across three biologically independent replicates (done in triplicate), with >100 animals assayed per plate.
FIG 2 TDP-1 limits RNAi by limiting nuclear RNAi. (A) (Top) Representative examples of GFP fluorescence in the untreated progeny (L4) of GFP RNAi-treated parents expressing a myo-3::GFP transgene in wild-type and tdp-1(ok803) backgrounds. (Bottom) Western blots of total proteins from 48-h-old untreated progeny of wild-type and tdp-1(ok803) animals treated with GFP feeding RNAi or empty vector. CPF-1 is a loading control. (B) Percentages of animals affected by lir-1 feeding RNAi. A schematic of the operon containing lir-1 and lin-26 is shown at the top. Boxes indicate genes, and the line represents the intercistronic space. The P value was calculated by Student's t test. (C) Loss of NRDE-3 function reverses the enhanced RNAi efficiency of the tdp-1(ok803) mutant. Genes targeted by RNAi in the indicated strains are shown on the x axis. P values were calculated by comparing values for the tdp-1(ok803) mutant alone to those for the tdp-1(ok803); nrde-3(gg66) double mutant by Student's t test. In panels B and C, error bars show SEM across three biologically independent replicates (done in triplicate), with >100 animals assayed per plate.CC BY · PubMed Central
FIG 3 tdp-1 and nrde-3 function redundantly to maintain health. (A) Fold changes (log2) in abundance of antisense (AS) siRNAs mapping to annotated genes between wild-type and tdp-1(ok803) mutants. Each dot represents an individual gene with an increased (red dots) or decreased (blue dots) abundance of AS siRNAs targeting that gene. (B) Example of a gene with increased antisense siRNA abundance in tdp-1(ok803) animals compared to that in wild-type animals. Blue boxes represent AS siRNA reads mapping to C41H7.6 in each sample. Coverage tracks are normalized to the total number of reads. (C and D) Average brood sizes for the indicated strains grown at 25°C (C) and 26°C (D). Broods were counted for at least 5 animals per strain, in triplicate, two independent times. Note that tdp-1(ok803); nrde-3(gg66) mutants are completely sterile at 26°C. (E) Number of thrashes counted per 30 s for each of the indicated strains. Also see Movies S1 and S2 in the supplemental material. Animals were grown from embryos at 25°C and scored as first-day adults. Thrashing was counted in at least 10 animals, in triplicate, two independent times. In panels C to E, error bars show SEM. *, P < 0.01 (calculated using one-way analysis of variance [ANOVA] with Tukey's highly significant difference [HSD] post hoc test).
FIG 3 tdp-1 and nrde-3 function redundantly to maintain health. (A) Fold changes (log2) in abundance of antisense (AS) siRNAs mapping to annotated genes between wild-type and tdp-1(ok803) mutants. Each dot represents an individual gene with an increased (red dots) or decreased (blue dots) abundance of AS siRNAs targeting that gene. (B) Example of a gene with increased antisense siRNA abundance in tdp-1(ok803) animals compared to that in wild-type animals. Blue boxes represent AS siRNA reads mapping to C41H7.6 in each sample. Coverage tracks are normalized to the total number of reads. (C and D) Average brood sizes for the indicated strains grown at 25°C (C) and 26°C (D). Broods were counted for at least 5 animals per strain, in triplicate, two independent times. Note that tdp-1(ok803); nrde-3(gg66) mutants are completely sterile at 26°C. (E) Number of thrashes counted per 30 s for each of the indicated strains. Also see Movies S1 and S2 in the supplemental material. Animals were grown from embryos at 25°C and scored as first-day adults. Thrashing was counted in at least 10 animals, in triplicate, two independent times. In panels C to E, error bars show SEM. *, P < 0.01 (calculated using one-way analysis of variance [ANOVA] with Tukey's highly significant difference [HSD] post hoc test).CC BY · PubMed Central
FIG 4 HPL-2 interacts directly with TDP-1. (A) Western blot probed with anti-TDP-1 (top panel) and anti-HPL-2 (middle panel) antibodies against protein immunoprecipitated with either anti-TDP-1 antibodies (lanes 3 to 6) or anti-HPL-2 antibodies (last three lanes) in extracts prepared from the indicated strains. IPs were performed with null tdp-1(ok803) and hpl-2(1489) mutant strains to control for nonspecific protein associations. The size of each protein is indicated. Note that HPL-2 runs slightly above the light chain band (∼26 kDa), even though HPL-2 is predicated to run at 21 kDa. The bottom panel was probed with secondary antibody only to show light chain-specific contamination. Treatment with both T1 (single-stranded RNA specific) and V1 (double-stranded RNA specific) RNases is indicated. Red arrows indicate a nonspecific background band recognized by the HPL-2 antibody used as an internal loading control. *, light chain contamination. (B) Correlation heat map showing high similarity between wild-type and tdp1(ok803) HPL-2 ChIP-seq replicates. Darker green shading indicates increased similarity. (C) Percentages of peaks in the indicated categories that were either increased or decreased for HPL-2 localization in tdp-1(ok803) mutants. ***, P < 1 × 10−10 (chi-square test). (D) Enriched binding motifs identified in HPL-2 ChIP-seq analyses of wild-type (left) and tdp-1(ok803) (right) animals, arranged according to decreasing P value. Sequences were filtered to keep the top five (by P value) unique motifs longer than 7 nt for both wild-type and tdp-1(ok803) animals. Red and green arrows indicate binding motifs identified in wild-type but not tdp-1(ok803) HPL-2 ChIP-seq experiments.
FIG 4 HPL-2 interacts directly with TDP-1. (A) Western blot probed with anti-TDP-1 (top panel) and anti-HPL-2 (middle panel) antibodies against protein immunoprecipitated with either anti-TDP-1 antibodies (lanes 3 to 6) or anti-HPL-2 antibodies (last three lanes) in extracts prepared from the indicated strains. IPs were performed with null tdp-1(ok803) and hpl-2(1489) mutant strains to control for nonspecific protein associations. The size of each protein is indicated. Note that HPL-2 runs slightly above the light chain band (∼26 kDa), even though HPL-2 is predicated to run at 21 kDa. The bottom panel was probed with secondary antibody only to show light chain-specific contamination. Treatment with both T1 (single-stranded RNA specific) and V1 (double-stranded RNA specific) RNases is indicated. Red arrows indicate a nonspecific background band recognized by the HPL-2 antibody used as an internal loading control. *, light chain contamination. (B) Correlation heat map showing high similarity between wild-type and tdp1(ok803) HPL-2 ChIP-seq replicates. Darker green shading indicates increased similarity. (C) Percentages of peaks in the indicated categories that were either increased or decreased for HPL-2 localization in tdp-1(ok803) mutants. ***, P < 1 × 10−10 (chi-square test). (D) Enriched binding motifs identified in HPL-2 ChIP-seq analyses of wild-type (left) and tdp-1(ok803) (right) animals, arranged according to decreasing P value. Sequences were filtered to keep the top five (by P value) unique motifs longer than 7 nt for both wild-type and tdp-1(ok803) animals. Red and green arrows indicate binding motifs identified in wild-type but not tdp-1(ok803) HPL-2 ChIP-seq experiments.CC BY · PubMed Central
FIG 5 TDP-1-dependent recruitment of HPL-2 to chromatin. Examples of introns that have TDP-1-dependent HPL-2 ChIP-seq peaks are shown. For each track, the coverage is normalized to the total number of reads. *, data were taken from reference 15 (accession number GSE61581).
FIG 5 TDP-1-dependent recruitment of HPL-2 to chromatin. Examples of introns that have TDP-1-dependent HPL-2 ChIP-seq peaks are shown. For each track, the coverage is normalized to the total number of reads. *, data were taken from reference 15 (accession number GSE61581).CC BY · PubMed Central
FIG 6 Overlapping transcriptome changes in tdp-1 and hpl-2 deletion mutants. (A) Venn diagram representing overlapping transcriptional changes in tdp-1(ok803) and hpl-2(tm1489) mutants (top) and bar graph illustrating that transcripts altered by both mutations are preferentially underexpressed (bottom). (B) Quantitative RT-PCR confirmation of selected transcripts with reduced accumulation in the tdp-1 and hpl-2 mutants relative to that in the wild type as identified by RNA-seq. For each transcript, primers were designed to target an exon, and amplification levels were normalized to the transcript level of pmp-3, a gene whose expression is not affected by the mutations tested. (C) Effects of TDP-1 and HPL-2 on the representative gene gsa-1. The green histogram displays ChIP-seq data for TDP-1 (15) (accession number GSE61581). Note the peak of TDP-1 binding localized over the second intron. Blue histograms display HPL-2 ChIP-seq data for wild-type (upper track) and tdp-1(ok803) (lower track) worms. Note the peak of HPL-2 binding in the second intron, which was lost in the tdp-1 deletion mutant. Black histograms display gsa-1 poly(A) transcript accumulation in wild-type, hpl-2(tm1489), and tdp-1(ok803) worms. Loss of HPL-2 resulted in a 6.8-fold reduction in gsa-1 transcripts, and loss of TDP-1 resulted in a 1.5-fold reduction. Red histograms display RIP-seq recovery of dsRNA transcripts (normalized to total RNA) for wild-type, hpl-2(tm1489), and tdp-1(ok803) worms. Note the large increases in dsRNA representation of gsa-1 transcripts with HPL-2 or TDP-1 loss. In panels B and C, error bars show SEM.
FIG 6 Overlapping transcriptome changes in tdp-1 and hpl-2 deletion mutants. (A) Venn diagram representing overlapping transcriptional changes in tdp-1(ok803) and hpl-2(tm1489) mutants (top) and bar graph illustrating that transcripts altered by both mutations are preferentially underexpressed (bottom). (B) Quantitative RT-PCR confirmation of selected transcripts with reduced accumulation in the tdp-1 and hpl-2 mutants relative to that in the wild type as identified by RNA-seq. For each transcript, primers were designed to target an exon, and amplification levels were normalized to the transcript level of pmp-3, a gene whose expression is not affected by the mutations tested. (C) Effects of TDP-1 and HPL-2 on the representative gene gsa-1. The green histogram displays ChIP-seq data for TDP-1 (15) (accession number GSE61581). Note the peak of TDP-1 binding localized over the second intron. Blue histograms display HPL-2 ChIP-seq data for wild-type (upper track) and tdp-1(ok803) (lower track) worms. Note the peak of HPL-2 binding in the second intron, which was lost in the tdp-1 deletion mutant. Black histograms display gsa-1 poly(A) transcript accumulation in wild-type, hpl-2(tm1489), and tdp-1(ok803) worms. Loss of HPL-2 resulted in a 6.8-fold reduction in gsa-1 transcripts, and loss of TDP-1 resulted in a 1.5-fold reduction. Red histograms display RIP-seq recovery of dsRNA transcripts (normalized to total RNA) for wild-type, hpl-2(tm1489), and tdp-1(ok803) worms. Note the large increases in dsRNA representation of gsa-1 transcripts with HPL-2 or TDP-1 loss. In panels B and C, error bars show SEM.CC BY · PubMed Central

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Metadata

Authors
Saldi, T. K., Gonzales, P., Garrido-Lecca, A., Dostal, V., Roberts, C. M., Petrucelli, L., & Link, C. D.
Affiliations
  • Department of Molecular, Cellular, and Developmental Biology, University of Colorado
  • Integrative Physiology, University of Colorado
  • Department of Neuroscience, Mayo Clinic
ORCID
Saldi, Tassa K.
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
2018-08-01
Volume
38
Issue
15
ISSN
1098-5549
DOI
10.1128/mcb.00668-17
PMC
PMC6048318
Cited by
16
References
6
Language
en
Licence
Funders
HHS | NIH | National Institute of Neurological Disorders and Stroke (R01 NS063964)

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CoChat. (2026). Citation check: The Caenorhabditis elegans Ortholog of TDP-43 Regulates the Chromatin Localization of the Heterochromatin Protein 1 Homolog HPL-2. https://app.cochat.ai/papers/10.1128/mcb.00668-17
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Saldi, T. K., Gonzales, P., Garrido-Lecca, A., Dostal, V., Roberts, C. M., Petrucelli, L., & Link, C. D. (2018). The Caenorhabditis elegans Ortholog of TDP-43 Regulates the Chromatin Localization of the Heterochromatin Protein 1 Homolog HPL-2. Molecular and Cellular Biology. https://doi.org/10.1128/mcb.00668-17

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