Epigenetic Compensation Promotes Liver Regeneration

Wang, Shuang; Zhang, Chi; Hasson, Dan; Desai, Anal; SenBanerjee, Sucharita; Magnani, Elena; Ukomadu, Chinweike; Lujambio, Amaia; Bernstein, Emily; Sadler, Kirsten C.

doi:10.1016/j.devcel.2019.05.034

Cited by 58 publications

(78 citation statements)

References 87 publications

(111 reference statements)

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“…These results indicate that removal of repressive marks 5mC and H3K27me3 as well as injury-induced changes of H3K4me3, which is associated with active promoters and hypomethylated promoters are the first step for the initial reprogramming of RPE. In accordance with the reduction of 5mC, we observed significant downregulation of DNMTs and the critical regulator of DNA methylation uhrf1, a factor that is associated with liver regeneration and redistribution of H3K27me3 from promoters to transposons [98]. Our results obtained at 6 hPR in t-rRPE partially recapitulate the results observed during fin regeneration in zebrafish, where the levels of 5mC and 5hmC were transiently reduced at 24 hours postamputation (hpa) in the blastema cells, and such reduction was also independent of proliferation [37].…”

Section: Discussionsupporting

confidence: 80%

DNA demethylation is a driver for chick retina regeneration

et al. 2020

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Cellular reprogramming resets the epigenetic landscape to drive shifts in transcriptional programmes and cell identity. The embryonic chick can regenerate a complete neural retina, after retinectomy, via retinal pigment epithelium (RPE) reprogramming in the presence of FGF2. In this study, we systematically analysed the reprogramming competent chick RPE prior to injury, and during different stages of reprogramming. In addition to changes in the expression of genes associated with epigenetic modifications during RPE reprogramming, we observed dynamic changes in histone marks associated with bivalent chromatin (H3K27me3/H3K4me3) and intermediates of the process of DNA demethylation including 5hmC and 5caC. Comprehensive analysis of the methylome by whole-genome bisulphite sequencing (WGBS) confirmed extensive rearrangements of DNA methylation patterns including differentially methylated regions (DMRs) found at promoters of genes associated with chromatin organization and fibroblast growth factor production. We also identified Tet methylcytosine dioxygenase 3 (TET3) as an important factor for DNA demethylation and retina regeneration, capable of reprogramming RPE in the absence of exogenous FGF2. In conclusion, we demonstrate that injury early in RPE reprogramming triggers genome-wide dynamic changes in chromatin, including bivalent chromatin and DNA methylation. In the presence of FGF2, these dynamic modifications are further sustained in the commitment to form a new retina. Our findings reveal active DNA demethylation as an important process that may be applied to remove the epigenetic barriers in order to regenerate retina in mammals.

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Section: Discussionsupporting

confidence: 80%

DNA demethylation is a driver for chick retina regeneration

et al. 2020

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“…These results indicate that removal of repressive marks 5mC and H3K27me3 as well as injury-induced changes of H3K4me3, which is associated with active promoters and hypomethylated promoters are the first step for the initial reprogramming of RPE. In accordance with the reduction of 5mC, we observed significant downregulation of DNMTs and the critical regulator of DNA methylation uhrf1, a factor that is associated with liver regeneration and redistribution of H3K27me3 from promoters to transposons [83]. Our results obtained at 6 hPR in t-rRPE, partially recapitulate the results observed during fin regeneration in zebrafish where the levels of 5mC and 5hmC were transiently reduced at 24 hours post-amputation (hpa) in the blastema cells, and such reduction was also independent of proliferation [37].…”

Section: Discussionsupporting

confidence: 80%

DNA demethylation is a driver for chick retina regeneration

Luz-Madrigal

Grajales-Esquivel

Tangeman

et al. 2019

Preprint

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ABSTRACTBackgroundA promising avenue toward human retina regeneration lies in identifying the factors that promote cellular reprogramming to retinal neurons in organisms able to undergo retina regeneration. The embryonic chick can regenerate a complete neural retina, after retinectomy, via retinal pigment epithelium (RPE) reprogramming in the presence of FGF2. Cellular reprogramming resets the epigenetic landscape to drive shifts in transcriptional programs and cell identity. Here, we systematically analyzed the reprogramming competent chick RPE prior to injury, and during different stages of reprogramming. We examined the dynamic changes in the levels and distribution of histone marks and DNA modifications, as well as conducted a comprehensive analysis of the DNA methylome during this process.ResultsIn addition to changes in the expression of genes associated with epigenetic modifications during RPE reprogramming, we observed dynamic changes in histone marks and intermediates of the process of DNA demethylation. At early times after injury, H3K27me3 and 5mC repression marks decreased while 5caC and the H3K4me3 activation mark increased, suggesting genome-wide changes in the bivalent chromatin, impaired DNA methylation, and active DNA demethylation in the chromatin reconfiguration of reprogramming RPE. Comprehensive analysis of the methylome by whole-genome bisulfite sequencing (WGBS) confirmed extensive rearrangements of DNA methylation patterns including differentially methylated regions (DMRs) found at promoters of genes associated with chromatin organization and fibroblast growth factor production. In contrast, genes associated with early RPE reprogramming are hypomethylated in the intact RPE and remain hypomethylated during the process. During the generation of a neuroepithelium (NE) at later stages of reprogramming, decreased levels of H3K27me3, 5mC, and 5hmC coincide with elevated levels of H3K27Ac and 5caC, indicating an active demethylation process and genome-wide changes in the active regulatory landscape. Finally, we identify Tet methylcytosine dioxygenase 3 (TET3) as an important factor for DNA demethylation and retina regeneration in the embryonic chick, capable of reprogramming RPE in the absence of exogenous FGF2.ConclusionOur results demonstrated that injury signals early in RPE reprogramming trigger genome-wide dynamic changes in chromatin, including bivalent chromatin and DNA methylation. In the presence of FGF2 these dynamic modifications are further sustained in the commitment to form a new retina. We identify DNA demethylation as a key process driving the process of RPE reprogramming and identified TET3 as a factor able to reprogram RPE in absence of FGF2. Our findings reveal active DNA demethylation as an important process that may be applied to remove the epigenetic barriers in order to regenerate retina in mammals.

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“…Heat maps analysis were generated using Easeq software. The following published ChIP-seq datasets were used: GSM2339529 (SETDB1 ChIP-Seq in Hepa 1.6 cells; Mus musculus; ChIP-Seq); GSM2339528 (KAP1 ChIP-Seq inHepa 1.6 cells; Mus musculus; ChIP-Seq); GSM2339536 (Total input Hepa 1.6 cells; Mus musculus; ChIP-Seq) (Kauzlaric et al, 2017); GSM3753284 (baseline WT H3K9me3); GSM3753283 (input WT H3K9me3) (Wang et al, 2019); GSM3679089 (WT H3K27Ac) and GSM3679121 (WT H3K4me1) (Praestholm et al, 2020).After re-analyzing all ChIPseqs using the same parameters as Zfp125 ChIP-seq, BED files were generated and used for heat map studies.…”

Section: Methodsmentioning

confidence: 99%

“…KRAB-ZFPs promote formation of heterochromatin by attracting co-repressors (Frietze et al, 2010;Seah et al, 2019;Sripathy et al, 2006). To test if this was the case with Zfp125, we used a published adult mouse liver dataset of the heterochromatin marker H3K9me3-ChIP-seq (Wang et al, 2019) and found a ~50% overlap with Zfp125 ChIP peaks ( Fig. 4A).…”

Section: Zfp125 Is a Transcriptional Repressor Of Metabolically Relatmentioning

confidence: 99%

The transcriptional repressor Zfp125 modifies hepatic energy metabolism in response to fasting and insulin resistance

Fernandes

Bocco

Fonseca

et al. 2020

Preprint

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SummaryZfp125 is a transcriptional repressor that inhibits hepatic VLDL secretion. Here we show that mice with liver-specific Zfp125 knockdown exhibited lower respiratory quotient, reduced glycemia and pyruvate-stimulated liver glucose output, and higher levels of β-hydroxyl-butyrate. Microarray and ChIP-seq studies identified Zfp125 peaks in the promoter of 135 metabolically relevant genes, including genes involved in fatty acid oxidation and ketogenesis, e.g. Ppara, Cpt1a, Bdh1 and Hmgcs2. Repression by Zfp125 involved recruitment of the corepressors Kap1 and the histone methyl transferase Setdb1, increasing the levels of H3K9me3, a heterochromatin marker of gene silencing. The resulting increase in acetyl-CoA levels accelerated gluconeogenesis through allosteric activation of pyruvate carboxylase. Zfp125 knockdown in isolated mouse hepatocytes amplified the induction of ketogenesis by glucagon or insulin resistance, whereas the expression of key gluconeogenic genes Pck1 and G6pc was amplified by Zfp125. These findings place Zfp125 at the center of fuel dysregulation of type 2 diabetes.

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Epigenetic Compensation Promotes Liver Regeneration

Cited by 58 publications

References 87 publications

DNA demethylation is a driver for chick retina regeneration

DNA demethylation is a driver for chick retina regeneration

DNA demethylation is a driver for chick retina regeneration

The transcriptional repressor Zfp125 modifies hepatic energy metabolism in response to fasting and insulin resistance

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