Association of UHRF1 with methylated H3K9 directs the maintenance of DNA methylation

Rothbart, Scott B.; Krajewski, Krzysztof; Nady, Nataliya; Tempel, W.; Xue, Song; Badeaux, Aimee I.; Baršytė-Lovejoy, Dalia; Martinez, Jorge Y.; Bedford, Mark T.; Fuchs, Stephen M.; Arrowsmith, C.H.; Strahl, Brian D.

doi:10.1038/nsmb.2391

Cited by 329 publications

(346 citation statements)

References 39 publications

Supporting

Mentioning

314

Contrasting

Unclassified

Order By: Relevance

“…As the activity of DNMT1 is stimulated by the binding of its cofactor, NP95, to H3K9me3 (Rothbart et al 2012(Rothbart et al , 2013, SETDB1-dependent deposition of this mark may also influence the efficiency of maintenance DNA methylation. Notably, NP95 expression is down-regulated in PGCs (Kurimoto et al 2008), and the remaining protein is detected predominantly in the cytoplasm (Seisenberger et al 2012), likely compromising maintenance methylation at a global level.…”

Section: Discussionmentioning

confidence: 99%

Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells

et al. 2014

View full text Add to dashboard Cite

Transcription of endogenous retroviruses (ERVs) is inhibited by de novo DNA methylation during gametogenesis, a process initiated after birth in oocytes and at approximately embryonic day 15.5 (E15.5) in prospermatogonia. Earlier in germline development, the genome, including most retrotransposons, is progressively demethylated. Young ERVK and ERV1 elements, however, retain intermediate methylation levels. As DNA methylation reaches a low point in E13.5 primordial germ cells (PGCs) of both sexes, we determined whether retrotransposons are marked by H3K9me3 and H3K27me3 using a recently developed low-input ChIP-seq (chromatin immunoprecipitation [ChIP] combined with deep sequencing) method. Although these repressive histone modifications are found predominantly on distinct genomic regions in E13.5 PGCs, they concurrently mark partially methylated long terminal repeats (LTRs) and LINE1 elements. Germline-specific conditional knockout of the H3K9 methyltransferase SETDB1 yields a decrease of both marks and DNA methylation at H3K9me3-enriched retrotransposon families. Strikingly, Setdb1 knockout E13.5 PGCs show concomitant derepression of many marked ERVs, including intracisternal A particle (IAP), ETn, and ERVK10C elements, and ERV-proximal genes, a subset in a sex-dependent manner. Furthermore, Setdb1 deficiency is associated with a reduced number of male E13.5 PGCs and postnatal hypogonadism in both sexes. Taken together, these observations reveal that SETDB1 is an essential guardian against proviral expression prior to the onset of de novo DNA methylation in the germline.

show abstract

Section: Discussionmentioning

confidence: 99%

Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells

et al. 2014

View full text Add to dashboard Cite

show abstract

“…It has recently been reported that knockdown of UHRF1 leads to a dramatic decrease in DNMT1 (20). Indeed, qRT-PCR and immunoblotting analyses revealed that knockdown of UPAT resulted in a drastic decrease in the levels of DNMT1 protein, but not mRNA, in HCT116 cells (Fig.…”

Section: Significancementioning

confidence: 99%

Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1

Taniue

Kurimoto

Sugimasa

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

137

127

View full text Add to dashboard Cite

Many long noncoding RNAs (lncRNAs) are reported to be dysregulated in human cancers and play critical roles in tumor development and progression. Furthermore, it has been reported that many lncRNAs regulate gene expression by recruiting chromatin remodeling complexes to specific genomic loci or by controlling transcriptional or posttranscriptional processes. Here we show that an lncRNA termed UPAT [ubiquitin-like plant homeodomain (PHD) and really interesting new gene (RING) finger domaincontaining protein 1 (UHRF1) Protein Associated Transcript] is required for the survival and tumorigenicity of colorectal cancer cells. UPAT interacts with and stabilizes the epigenetic factor UHRF1 by interfering with its β-transducin repeat-containing protein (TrCP)-mediated ubiquitination. Furthermore, we demonstrate that UHRF1 up-regulates Stearoyl-CoA desaturase 1 and Sprouty 4, which are required for the survival of colon tumor cells. Our study provides evidence for an lncRNA that regulates protein ubiquitination and degradation and thereby plays a critical role in the survival and tumorigenicity of tumor cells. Our results suggest that UPAT and UHRF1 may be promising molecular targets for the therapy of colon cancer.A mong the RNA products transcribed from the mammalian genome are numerous long noncoding RNAs (lncRNAs)-that is, RNAs longer than 200 nucleotides with little or no protein-coding potential (1, 2). Many lncRNAs are expressed in a developmentally regulated and cell type-dependent manner (3, 4). Increasing evidence suggests that lncRNAs play critical roles in a diverse set of biological processes, including proliferation, differentiation, embryogenesis, neurogenesis, and stem cell pluripotency (5, 6).It has been reported that many lncRNAs regulate gene expression by recruiting chromatin remodeling complexes to specific genomic regions (2). It has also been shown that many lncRNAs regulate transcription by modulating the activity of transcriptional regulators (1, 6-8). lncRNAs also regulate various posttranscriptional processes, including splicing, transport, translation, and degradation of mRNA. Furthermore, recent studies have shown that a number of lncRNAs play critical roles in tumor development and progression.UHRF1 [ubiquitin-like plant homeodomain (PHD) and really interesting new gene (RING) finger domain-containing protein 1] is an epigenetic factor that consists of multiple domains (9). UHRF1 regulates transcription by regulating DNA methylation and histone modification. UHRF1 also possesses E3 ubiquitin ligase activity and ubiquitinates histones and DNA methyltransferase 1 (DNMT1), thereby regulating the chromatin structure and stability of DNMT1 (10, 11). UHRF1 plays key roles in multiple biological processes, including proliferation and development. Furthermore, UHRF1 is overexpressed in various tumors, including colon, breast, bladder, prostate, and lung cancers, and plays a critical role in the proliferation and survival of tumor cells (9).In the present study, we attempted to identify lncRNAs criti...

show abstract

“…Genetic studies have demonstrated that UHRF1 is essential for faithful DNMT1-mediated maintenance methylation (Bostick et al 2007;Sharif et al 2007), and our laboratory determined that the DNA methylation maintenance function of UHRF1 is linked to its ability to engage di-and trimethylated H3K9 (H3K9me2/3)-transcriptionally repressive chromatin marks enriched at pericentric heterochromatin and telomeres (Ebert et al 2006;Grewal and Elgin 2007;Hawkins et al 2010;Ernst et al 2011)-through the first Tudor subdomain of its tandem Tudor domain (TTD) (Fig. 1A,B; Nady et al 2011;Rothbart et al 2012a). The adjacent PHD of UHRF1 (Fig.…”

mentioning

confidence: 99%

Multivalent histone engagement by the linked tandem Tudor and PHD domains of UHRF1 is required for the epigenetic inheritance of DNA methylation

et al. 2013

Self Cite

View full text Add to dashboard Cite

Histone post-translational modifications regulate chromatin structure and function largely through interactions with effector proteins that often contain multiple histone-binding domains. While significant progress has been made characterizing individual effector domains, the role of paired domains and how they function in a combinatorial fashion within chromatin are poorly defined. Here we show that the linked tandem Tudor and plant homeodomain (PHD) of UHRF1 (ubiquitin-like PHD and RING finger domain-containing protein 1) operates as a functional unit in cells, providing a defined combinatorial readout of a heterochromatin signature within a single histone H3 tail that is essential for UHRF1-directed epigenetic inheritance of DNA methylation. These findings provide critical support for the ''histone code'' hypothesis, demonstrating that multivalent histone engagement plays a key role in driving a fundamental downstream biological event in chromatin.

show abstract

Association of UHRF1 with methylated H3K9 directs the maintenance of DNA methylation

Cited by 329 publications

References 39 publications

Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells

Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells

Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1

Multivalent histone engagement by the linked tandem Tudor and PHD domains of UHRF1 is required for the epigenetic inheritance of DNA methylation

Contact Info

Product

Resources

About