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The histone demethylase Jhdm1a regulates hepatic gluconeogenesis.

Pan D, Mao C, Zou T, Yao AY, Cooper MP, Boyartchuk V, Wang YX - PLoS Genet. (2012)

Bottom Line: In vivo, silencing of Jhdm1a promotes liver glucose synthesis, while its exogenous expression reduces blood glucose level.Importantly, the regulation of gluconeogenesis by Jhdm1a requires its demethylation activity.This is achieved, at least in part, by its USF1-dependent association with the C/EBPα promoter and its subsequent demethylation of dimethylated H3K36 on the C/EBPα locus.

View Article: PubMed Central - PubMed

Affiliation: Program in Gene Function and Expression and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.

ABSTRACT
Hepatic gluconeogenesis is required for maintaining blood glucose homeostasis; yet, in diabetes mellitus, this process is unrestrained and is a major contributor to fasting hyperglycemia. To date, the impacts of chromatin modifying enzymes and chromatin landscape on gluconeogenesis are poorly understood. Through catalyzing the removal of methyl groups from specific lysine residues in the histone tail, histone demethylases modulate chromatin structure and, hence, gene expression. Here we perform an RNA interference screen against the known histone demethylases and identify a histone H3 lysine 36 (H3K36) demethylase, Jhdm1a, as a key negative regulator of gluconeogenic gene expression. In vivo, silencing of Jhdm1a promotes liver glucose synthesis, while its exogenous expression reduces blood glucose level. Importantly, the regulation of gluconeogenesis by Jhdm1a requires its demethylation activity. Mechanistically, we find that Jhdm1a regulates the expression of a major gluconeogenic regulator, C/EBPα. This is achieved, at least in part, by its USF1-dependent association with the C/EBPα promoter and its subsequent demethylation of dimethylated H3K36 on the C/EBPα locus. Our work provides compelling evidence that links histone demethylation to transcriptional regulation of gluconeogenesis and has important implications for the treatment of diabetes.

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Jhdm1a specifically demethylates dimethylated H3K36 on the C/EBPα locus.(A) Knockdown of Jhdm1a increases H3K36 dimethylation (H3K36me2) on the C/EBPα locus. Data were shown from one representative of three independent experiments with similar results. (B) Knockdown of Jhdm1a does not affect H3K36me2 on the C/EBPβ locus. (C) Knockdown of Jhdm1a does not increase H3K36 trimethylation (H3K36me3) on the C/EBPα locus. (D) Wild-type Jhdm1a, but not the H212A point mutant, decreases H3K36me2 on the C/EBPα locus. (E) H3K36me2 on the C/EBPα locus is not modulated by feeding/fasting conditions. n = 4 per group. (F) Decreased H3K36me2 on the C/EBPα locus in ob/ob mice. n = 4 per group. **, P<0.01.
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pgen-1002761-g006: Jhdm1a specifically demethylates dimethylated H3K36 on the C/EBPα locus.(A) Knockdown of Jhdm1a increases H3K36 dimethylation (H3K36me2) on the C/EBPα locus. Data were shown from one representative of three independent experiments with similar results. (B) Knockdown of Jhdm1a does not affect H3K36me2 on the C/EBPβ locus. (C) Knockdown of Jhdm1a does not increase H3K36 trimethylation (H3K36me3) on the C/EBPα locus. (D) Wild-type Jhdm1a, but not the H212A point mutant, decreases H3K36me2 on the C/EBPα locus. (E) H3K36me2 on the C/EBPα locus is not modulated by feeding/fasting conditions. n = 4 per group. (F) Decreased H3K36me2 on the C/EBPα locus in ob/ob mice. n = 4 per group. **, P<0.01.

Mentions: Given the association of Jhdm1a with the C/EBPα promoter, we examined whether Jhdm1a modulates the H3K36 methylation pattern on the C/EBPα locus. Knockdown of Jhdm1a increased H3K36 dimethylation in the 3′ exon region and 3′ UTR that is close to the exon, but had little effect on H3K36 dimethylation on the promoter, 5′ exon region, and 3′UTR that is located far away from the exon (Figure 6A). This pattern of modulation is in concord with the previously shown genome-wide distribution of H3K36 dimethylation where it is mostly found in the intragenic region and usually peaks toward 3′ exon [15]. The demethylation by Jhdm1a is gene-specific, as knockdown of Jhdm1a did not increase H3K36 dimethylation at the C/EBPβ locus (Figure 6B). Moreover, knockdown of Jhdm1a did not affect the H3K36 trimethylation pattern at the C/EBPα locus (Figure 6C), consistent with the enzymatic property of Jhdm1a to specifically demethylate dimethylated H3K36 [20]. Next, we examined the effect of ectopically expressed Jhdm1a on H3K36 dimethylation at the C/EBPα locus. We found that expression of wild type Jhdm1a, but not of the H212A mutant, led to a significant decrease of K36 dimethylation (Figure 6D). These results suggest that Jhdm1a demethylates dimethylated H3K36 at the C/EBPα locus, hence directly regulating its expression.


The histone demethylase Jhdm1a regulates hepatic gluconeogenesis.

Pan D, Mao C, Zou T, Yao AY, Cooper MP, Boyartchuk V, Wang YX - PLoS Genet. (2012)

Jhdm1a specifically demethylates dimethylated H3K36 on the C/EBPα locus.(A) Knockdown of Jhdm1a increases H3K36 dimethylation (H3K36me2) on the C/EBPα locus. Data were shown from one representative of three independent experiments with similar results. (B) Knockdown of Jhdm1a does not affect H3K36me2 on the C/EBPβ locus. (C) Knockdown of Jhdm1a does not increase H3K36 trimethylation (H3K36me3) on the C/EBPα locus. (D) Wild-type Jhdm1a, but not the H212A point mutant, decreases H3K36me2 on the C/EBPα locus. (E) H3K36me2 on the C/EBPα locus is not modulated by feeding/fasting conditions. n = 4 per group. (F) Decreased H3K36me2 on the C/EBPα locus in ob/ob mice. n = 4 per group. **, P<0.01.
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pgen-1002761-g006: Jhdm1a specifically demethylates dimethylated H3K36 on the C/EBPα locus.(A) Knockdown of Jhdm1a increases H3K36 dimethylation (H3K36me2) on the C/EBPα locus. Data were shown from one representative of three independent experiments with similar results. (B) Knockdown of Jhdm1a does not affect H3K36me2 on the C/EBPβ locus. (C) Knockdown of Jhdm1a does not increase H3K36 trimethylation (H3K36me3) on the C/EBPα locus. (D) Wild-type Jhdm1a, but not the H212A point mutant, decreases H3K36me2 on the C/EBPα locus. (E) H3K36me2 on the C/EBPα locus is not modulated by feeding/fasting conditions. n = 4 per group. (F) Decreased H3K36me2 on the C/EBPα locus in ob/ob mice. n = 4 per group. **, P<0.01.
Mentions: Given the association of Jhdm1a with the C/EBPα promoter, we examined whether Jhdm1a modulates the H3K36 methylation pattern on the C/EBPα locus. Knockdown of Jhdm1a increased H3K36 dimethylation in the 3′ exon region and 3′ UTR that is close to the exon, but had little effect on H3K36 dimethylation on the promoter, 5′ exon region, and 3′UTR that is located far away from the exon (Figure 6A). This pattern of modulation is in concord with the previously shown genome-wide distribution of H3K36 dimethylation where it is mostly found in the intragenic region and usually peaks toward 3′ exon [15]. The demethylation by Jhdm1a is gene-specific, as knockdown of Jhdm1a did not increase H3K36 dimethylation at the C/EBPβ locus (Figure 6B). Moreover, knockdown of Jhdm1a did not affect the H3K36 trimethylation pattern at the C/EBPα locus (Figure 6C), consistent with the enzymatic property of Jhdm1a to specifically demethylate dimethylated H3K36 [20]. Next, we examined the effect of ectopically expressed Jhdm1a on H3K36 dimethylation at the C/EBPα locus. We found that expression of wild type Jhdm1a, but not of the H212A mutant, led to a significant decrease of K36 dimethylation (Figure 6D). These results suggest that Jhdm1a demethylates dimethylated H3K36 at the C/EBPα locus, hence directly regulating its expression.

Bottom Line: In vivo, silencing of Jhdm1a promotes liver glucose synthesis, while its exogenous expression reduces blood glucose level.Importantly, the regulation of gluconeogenesis by Jhdm1a requires its demethylation activity.This is achieved, at least in part, by its USF1-dependent association with the C/EBPα promoter and its subsequent demethylation of dimethylated H3K36 on the C/EBPα locus.

View Article: PubMed Central - PubMed

Affiliation: Program in Gene Function and Expression and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.

ABSTRACT
Hepatic gluconeogenesis is required for maintaining blood glucose homeostasis; yet, in diabetes mellitus, this process is unrestrained and is a major contributor to fasting hyperglycemia. To date, the impacts of chromatin modifying enzymes and chromatin landscape on gluconeogenesis are poorly understood. Through catalyzing the removal of methyl groups from specific lysine residues in the histone tail, histone demethylases modulate chromatin structure and, hence, gene expression. Here we perform an RNA interference screen against the known histone demethylases and identify a histone H3 lysine 36 (H3K36) demethylase, Jhdm1a, as a key negative regulator of gluconeogenic gene expression. In vivo, silencing of Jhdm1a promotes liver glucose synthesis, while its exogenous expression reduces blood glucose level. Importantly, the regulation of gluconeogenesis by Jhdm1a requires its demethylation activity. Mechanistically, we find that Jhdm1a regulates the expression of a major gluconeogenic regulator, C/EBPα. This is achieved, at least in part, by its USF1-dependent association with the C/EBPα promoter and its subsequent demethylation of dimethylated H3K36 on the C/EBPα locus. Our work provides compelling evidence that links histone demethylation to transcriptional regulation of gluconeogenesis and has important implications for the treatment of diabetes.

Show MeSH
Related in: MedlinePlus