Project description:Sexual dimorphism of gene expression is commonly observed in mammalian tissues, including liver. To assess sexual dimorphisms in gene expression, we profiled the transcriptome of liver tissue from 20-week old male and female mice of the C57BL/6N (B6) and C3H/HeN (C3) inbred mouse strains using RNA-seq. These two inbred mouse strains exhibit phenotypic differences in liver biology, as they are at opposite ends of the spectrum of spontaneous hepatocellular carcinoma incidence; C3 mice are highly susceptible to develop spontaneous liver tumors as a function of age, while B6 mice are extremely resistant. Overall, these datasets provide insight into the underlying gene expression patterns that should be considered when assessing sex differences in mouse liver.
Project description:Here we map six chromatin modifications -- H3K4me1, H3K4me3, H3K27ac, H3K36me3, H3K9me3, and H3K27me3 -- genome-wide in male and female mouse liver in order to identify histone modifications that characterize sex-biased genes and sex-biased DNase hypersensitive sites and their regulation by plasma growth hormone (GH) profiles, which are sexually dimorphic. We find distinct mechanisms of regulation in male liver and female liver: sex-dependent K27me3-mediated repression is an important mechanism of repression of female-biased, but not of male-biased, genes, and a sex-dependent K4me1 distribution, suggesting nucleosome repositioning by pioneer factors, is observed at male-biased, but not female-biased, regulatory sites. STAT5-mediated activation is most strongly associated with sex-biased chromatin modifications, while BCL6-mediated repression primarily occurs in association with sex-independent chromatin modifications, both at binding sites and at target genes. These samples are part of a study on chromatin states in male and female mouse and their role in sex-biased liver gene expression (A Sugathan and DJ Waxman (2013) Molec Cell Biol).
Project description:Growth hormone (GH)-regulated transcription factors, notably STAT5 and BCL6, play a major role in regulating genes showing sex differences in expression in mouse liver, primarily through their effects in male liver, where male-biased genes are up regulated and many female-biased genes are actively repressed. Here we investigate whether complementary mechanisms, involving up regulation of female-biased genes and down regulation of male-biased genes occur in female liver. To address this question, we identified genes regulated by Cux2, a highly female-specific transcription factor that is repressed in male liver and is induced by the female plasma GH pattern in female liver. ChIP-seq analysis identified Cux2 binding sites in female liver only, where they are enriched at sites of male-biased DNase hypersensitivity and at genomic regions showing male-enriched STAT5 binding. Cux2 binding sites were enriched at genes repressed by adenoviral-Cux2, but not at genes induced by adenoviral-Cux2 (see GSE35897), indicating a direct binding mechanism in Cux2 repression but not in Cux2-dependent gene induction. (Published in: TL Conforto et al 2012, Mol Cell Biol. 2012, 32:4611-4627. PubMed PMID: 22966202; PMCID: PMC3486175)
Project description:∼40,000 HNF6 binding sites were identified in mouse liver chromatin, including several thousand sites showing significant differences in level of HNF6 binding between male and female mouse liver. These sex-biased HNF6 binding sites showed strong enrichment for sex-biased DNase hypersensitive sites and for proximity to genes showing local sex-biased chromatin marks and a corresponding sex-biased expression. ~90% of genome-wide CUX2 binding sites identified previously in female mouse liver (Conforto TL, Zhang Y, Sherman J, Waxman DJ., Mol Cell Biol. 2012;32(22):4611-4627) were also bound by HNF6, giving evidence for genome-wide competition between HNF6 and CUX2 for chromatin binding in female mouse liver. These HNF6/CUX2 common binding sites were enriched for genomic regions more accessible in male than in female mouse liver chromatin, and showed strongest enrichment for male-biased genes, suggesting HNF6 displacement by CUX2 as a mechanism to explain the observed CUX2 repression of male-biased genes in female liver. However, HNF6 binding was sex-independent at a majority of its binding sites, and peak regions of HNF6 binding were frequently associated with co-binding by multiple other liver transcription factors, consistent with HNF6 playing a global regulatory role in both male and female liver.
Project description:Here we map six chromatin modifications -- H3K4me1, H3K4me3, H3K27ac, H3K36me3, H3K9me3, and H3K27me3 -- genome-wide in male and female mouse liver in order to identify histone modifications that characterize sex-biased genes and sex-biased DNase hypersensitive sites and their regulation by plasma growth hormone (GH) profiles, which are sexually dimorphic. We find distinct mechanisms of regulation in male liver and female liver: sex-dependent K27me3-mediated repression is an important mechanism of repression of female-biased, but not of male-biased, genes, and a sex-dependent K4me1 distribution, suggesting nucleosome repositioning by pioneer factors, is observed at male-biased, but not female-biased, regulatory sites. STAT5-mediated activation is most strongly associated with sex-biased chromatin modifications, while BCL6-mediated repression primarily occurs in association with sex-independent chromatin modifications, both at binding sites and at target genes. These samples are part of a study on chromatin states in male and female mouse and their role in sex-biased liver gene expression (A Sugathan and DJ Waxman (2013) Molec Cell Biol). Examination of six different histone modifications in male and female mouse liver.
Project description:Gene expression in adult male and female mouse liver was assayed by RNA-seq, as part of a study on chromatin states in male and female mouse and their role in sex-biased liver gene expression (A Sugathan and DJ Waxman (2013) Mol Cell Biol. 33:3594-3610. doi: 10.1128/MCB.00280-13).
Project description:Growth hormone (GH)-regulated transcription factors, notably STAT5 and BCL6, play a major role in regulating genes showing sex differences in expression in mouse liver, primarily through their effects in male liver, where male-biased genes are up regulated and many female-biased genes are actively repressed. Here we investigate whether complementary mechanisms, involving up regulation of female-biased genes and down regulation of male-biased genes occur in female liver. To address this question, we identified genes regulated by Cux2, a highly female-specific transcription factor that is repressed in male liver and is induced by the female plasma GH pattern in female liver. ChIP-seq analysis identified Cux2 binding sites in female liver only, where they are enriched at sites of male-biased DNase hypersensitivity and at genomic regions showing male-enriched STAT5 binding. Cux2 binding sites were enriched at genes repressed by adenoviral-Cux2, but not at genes induced by adenoviral-Cux2 (see GSE35897), indicating a direct binding mechanism in Cux2 repression but not in Cux2-dependent gene induction. (Published in: TL Conforto et al 2012, Mol Cell Biol. 2012, 32:4611-4627. PubMed PMID: 22966202; PMCID: PMC3486175) Mouse livers were excised from individual male and female. Sonicated, cross-linked liver nuclear chromatin was then used to identify Cux2 binding sites by ChIP-Seq using antibody specific to Cux2, amino acids 356 to 415
Project description:∼40,000 HNF6 binding sites were identified in mouse liver chromatin, including several thousand sites showing significant differences in level of HNF6 binding between male and female mouse liver. These sex-biased HNF6 binding sites showed strong enrichment for sex-biased DNase hypersensitive sites and for proximity to genes showing local sex-biased chromatin marks and a corresponding sex-biased expression. ~90% of genome-wide CUX2 binding sites identified previously in female mouse liver (Conforto TL, Zhang Y, Sherman J, Waxman DJ., Mol Cell Biol. 2012;32(22):4611-4627) were also bound by HNF6, giving evidence for genome-wide competition between HNF6 and CUX2 for chromatin binding in female mouse liver. These HNF6/CUX2 common binding sites were enriched for genomic regions more accessible in male than in female mouse liver chromatin, and showed strongest enrichment for male-biased genes, suggesting HNF6 displacement by CUX2 as a mechanism to explain the observed CUX2 repression of male-biased genes in female liver. However, HNF6 binding was sex-independent at a majority of its binding sites, and peak regions of HNF6 binding were frequently associated with co-binding by multiple other liver transcription factors, consistent with HNF6 playing a global regulatory role in both male and female liver. Livers were excised from individual male and female mice, cross-linked and sonicated, then used to identify HNF6 binding sites by ChIP-Seq using antibody specific to HNF6 (sc-13050; Santa Cruz Biotechnology, Inc).