R loops regulate promoter-proximal chromatin architecture and cellular differentiation

Chen, Poshen B.; Chen, Hsiuyi V.; Acharya, Diwash; Rando, Oliver J.; Fazzio, Thomas G.

doi:10.1038/nsmb.3122

Cited by 161 publications

(202 citation statements)

References 54 publications

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“…These data reveal that normal binding of Tip60-p400 to most target genes depends on R-loops. 20 Together with our findings that Tip60-p400 binds to nascent RNAs, these studies suggest Tip60-p400 may be recruited to genes in part via direct interaction with the RNA component of promoter-proximal R-loops (Fig. 1).…”

Section: R-loops Promote the Activities Of Some Chromatin Regulatory supporting

confidence: 80%

“…However, we observed the opposite result-upon reduction of R-loops by over-expression of the Rnaseh1 gene to specifically degrade RNAs within RNA:DNA hybrids, PRC2 binding to most of its normal targets is enhanced, along with ectopic binding to many genes not normally targeted by the complex. 20 Combined with earlier findings, 29,30 these data suggest PRC2 binds to nascent RNAs that do not favor R-loop formation and that disruption of normal promoter-proximal chromatin structure by R-loops inhibits PRC2 binding (Fig. 1).…”

supporting

confidence: 76%

“…35 We recently showed that one of these complexes, the Tip60-p400 histone acetyltransferase and H2A.Z deposition complex, binds not only to lncRNAs, but also binds to approximately 2000 nascent transcripts from coding genes. 20 Interestingly, while many of the transcripts bound by Tip60-p400 were expressed at moderate to high levels, a portion of them were expressed at relatively low levels, suggesting the complex does not simply bind transcripts in proportion to their expression level. When we compared the genome-wide binding profiles of Tip60-p400 complex (which binds most prominently to promoter-proximal regions) to the presence of R-loops, we observed a strong association between the two.…”

Section: R-loops Promote the Activities Of Some Chromatin Regulatory mentioning

confidence: 98%

“…19 Besides these functions in DNA replication and recombination, recent studies from several labs have uncovered functions for R-loops in several different aspects of transcription. 3,13,15,20,21 While R-loops appear to regulate expression of genes by several different mechanisms, one common theme appears to be their ability to alter local chromatin structure.…”

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confidence: 99%

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Regulation of chromatin structure and cell fate by R-loops

Fazzio

2016

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Hybridization of RNA to its template DNA strand during transcription induces formation of R-loops-RNA:DNA hybrids with unpaired non-template DNA strands. Although unresolved R-loops can be detrimental, some R-loops contribute to regulation of chromatin structure. Consequently, R-loops help regulate gene expression and play important roles in numerous cellular processes. 1 Studies have shown that R-loop accumulation in vivo is favored by G-rich transcripts.2,3 At least two structural features of R-loops may contribute to this observation. First, purine-rich RNAs hybridized to pyrimidine-rich DNA strands (rR:dY) adopt a conformation close to the highly stable A-form structure of RNA:RNA hybrids and are much more thermodynamically stable than rY:dR hybrids or DNA duplexes of the same sequence.4,5 Second, G-rich sequences on the displaced non-template DNA strand may be stabilized by formation of G-quadruplex structures.6 Therefore, given the access of nascent transcripts to their unwound, complementary templates during transcription, and the favorable energetics of RNA:DNA hybrid formation, it is perhaps not surprising that transcription-associated R-loops can be observed in eukaryotes from yeast to humans, as well as prokaryotes. 7Unresolved R-loops induce DNA single-and double-strand breaks, higher mutation rates, and genomic instability. 7-10Consequently, cells have evolved multiple mechanisms for regulating the accumulation of R-loops that help prevent mutations, DNA damage, and genomic instability. With the exception of the CRISPR/Cas system, 11 all regulators of R-loops that have been identified appear to act negatively-removing R-loops that have formed or preventing R-loop formation.7 One prominent example includes the DNA:RNA helicase SETX (Sen1 in yeast). SETX melts the RNA:DNA duplex of R-loops, 12 which can be accompanied by degradation of the transcript by the RNA exonuclease, Xrn2.13 A second method of Rloop removal is through the actions of RNase H enzymes (RNase H1 and RNase H2 in eukaryotes), which degrade the RNA strand of the duplex through their endonuclease activities.14 It is not known whether additional proteins exist that specifically promote R-loop stability, either directly or by counteracting the functions of proteins that destabilize R-loops.Despite these mechanisms of R-loop removal, Rloops accumulate at multiple regions of the genome, particularly near the transcription start sites (TSSs) and transcription termination sites (TTSs) of transcribed genes.2,3,13,15 Steady-state R-loop levels are therefore likely a function of the combined effects of biophysical properties of the particular RNA:DNA hybrid, the level of transcription of the RNA component of the R-loop, and the presence or absence of proteins that inhibit R-loop formation or disrupt R-loops CONTACT Thomas G. Fazzio

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Section: R-loops Promote the Activities Of Some Chromatin Regulatory supporting

confidence: 80%

supporting

confidence: 76%

Section: R-loops Promote the Activities Of Some Chromatin Regulatory mentioning

confidence: 98%

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confidence: 99%

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Regulation of chromatin structure and cell fate by R-loops

Fazzio

2016

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“…It has been proposed that this type of chromo barrel/Tudor-like domain can recognize DNA and RNA (73,74), including that of Esa1 (75; C. Gallo, N. Lacoste, J. Côté, and J. Smith, unpublished data). Strikingly, the mammalian NuA4 complex, Tip60-p400, was recently shown to bind R loops formed by nascent transcripts at the beginning of genes, which explains in part its transcription-dependent binding to these regions (76). It will be very interesting to verify whether this occurs in yeast and if it is dependent on the Esa1 chromodomain.…”

Section: Discussionmentioning

confidence: 98%

Combined Action of Histone Reader Modules Regulates NuA4 Local Acetyltransferase Function but Not Its Recruitment on the Genome

Steunou

Cramet

Rossetto

et al. 2016

Molecular and Cellular Biology

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e Recognition of histone marks by reader modules is thought to be at the heart of epigenetic mechanisms. These protein domains are considered to function by targeting regulators to chromosomal loci carrying specific histone modifications. This is important for proper gene regulation as well as propagation of epigenetic information. The NuA4 acetyltransferase complex contains two of these reader modules, an H3K4me3-specific plant homeodomain (PHD) within the Yng2 subunit and an H3K36me2/3-specific chromodomain in the Eaf3 subunit. While each domain showed a close functional interaction with the respective histone mark that it recognizes, at the biochemical level, genetic level (as assessed with epistatic miniarray profile screens), and phenotypic level, cells with the combined loss of both readers showed greatly enhanced phenotypes. Chromatin immunoprecipitation coupled with next-generation sequencing experiments demonstrated that the Yng2 PHD specifically directs H4 acetylation near the transcription start site of highly expressed genes, while Eaf3 is important downstream on the body of the genes. Strikingly, the recruitment of the NuA4 complex to these loci was not significantly affected. Furthermore, RNA polymerase II occupancy was decreased only under conditions where both PHD and chromodomains were lost, generally in the second half of the gene coding regions. Altogether, these results argue that methylated histone reader modules in NuA4 are not responsible for its recruitment to the promoter or coding regions but, rather, are required to orient its acetyltransferase catalytic site to the methylated histone 3-bearing nucleosomes in the surrounding chromatin, cooperating to allow proper transition from transcription initiation to elongation. Chromatin is a dynamic nucleoprotein structure that compacts the long DNA molecule into the small nuclear space, simultaneously creating a mechanism to regulate DNA access to machineries implicated in essential nuclear processes, namely, transcription, DNA replication, DNA repair, and meiotic recombination. Modulation of the chromatin structure is highly regulated by four broad classes of nuclear factors: chromatin remodelers, histone chaperones, histone variants, and histone modifiers. These players essentially target nucleosomes, basic units of chromatin consisting of 146 bp of DNA wrapped around an octamer of histone proteins. Histone modifiers catalyze posttranslational modifications (PTM), including acetylation, phosphorylation, and methylation, that can directly affect DNA-histone contacts (e.g., acetylation) and/or create a binding platform for PTM readers (1, 2). These readers correspond to proteins/complexes containing distinct domains/modules that can bind specific modified histone residues. Such motifs include bromodomains that recognize acetylated residues; chromodomains (CHD); PWWP, Tudor, and MBT domains for methylated residues; BRCT, BIR, and 14-3-3 domains for phosphorylated histones; and plant homeodomain (PHD) fingers that can bind different modification...

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Looping forward: exploring R‐loop processing and therapeutic potential

Stratigi,

Siametis,

Garinis

2024

FEBS Letters

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Recently, there has been increasing interest in the complex relationship between transcription and genome stability, with specific attention directed toward the physiological significance of molecular structures known as R‐loops. These structures arise when an RNA strand invades into the DNA duplex, and their formation is involved in a wide range of regulatory functions affecting gene expression, DNA repair processes or cell homeostasis. The persistent presence of R‐loops, if not effectively removed, contributes to genome instability, underscoring the significance of the factors responsible for their resolution and modification. In this review, we provide a comprehensive overview of how R‐loop processing can drive either a beneficial or a harmful outcome. Additionally, we explore the potential for manipulating such structures to devise rationalized therapeutic strategies targeting the aberrant accumulation of R‐loops.

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R loops regulate promoter-proximal chromatin architecture and cellular differentiation

Cited by 161 publications

References 54 publications

Regulation of chromatin structure and cell fate by R-loops

Regulation of chromatin structure and cell fate by R-loops

Combined Action of Histone Reader Modules Regulates NuA4 Local Acetyltransferase Function but Not Its Recruitment on the Genome

Looping forward: exploring R‐loop processing and therapeutic potential

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