Repeat after Me(CP2)!

doi:10.1126/science.abj5027

GSTDTAP > 气候变化

DOI	10.1126/science.abj5027
	Repeat after Me(CP2)!
	Jian Zhou; Huda Zoghbi
	2021-06-25
发表期刊	Science
出版年	2021
英文摘要	Rett syndrome (RTT) is a devastating neurodevelopmental disease caused primarily by loss-of-function mutations in methyl-CpG-binding protein 2 ( MECP2 ) ([ 1 ][1]). MeCP2 is a DNA binding protein ([ 2 ][2]) that controls gene expression, but the precise molecular mechanism by which MeCP2 loss drives RTT pathology remains unclear, partially because a distinct DNA motif that specifies MeCP2-DNA interactions is lacking. On page 1411 of this issue, Ibrahim et al. ([ 3 ][3]) demonstrate that MeCP2 binds modified cytosine in cytosine-adenine (CA) dinucleotide repeats, providing a new signature DNA motif for MeCP2 binding. MeCP2 protects CA repeats from high nucleosome occupancy, raising questions about the consequence of this binding on maintaining chromatin structure in neurons. MeCP2 was first characterized as binding to methylated cytosine residues in the context of cytosine-guanine (CG) dinucleotides. Many mutations in the methyl-CpG binding domain (MBD) of MeCP2 cause the most severe RTT phenotypes in patients and mouse models of the condition, indicating that DNA binding is essential to MeCP2 function ([ 4 ][4]–[ 6 ][5]). Later studies revealed that MeCP2 also binds methylated CH [mCH, where H is adenine (A), cytosine (C), or thymine (T)], hydroxymethylated CA (hmCA), and methylated or hydroxymethylated CAC ([ 7 ][6]–[ 9 ][7]). Unlike canonical transcription factors, the characterization of MeCP2 binding sites did not identify a signature motif. Because of this featureless binding pattern and high abundance of the protein—MeCP2 broadly coats the genome ([ 10 ][8])—it has been challenging to associate MeCP2 DNA binding with specific gene expression changes. Identifying the DNA sequences and modifications that specify MeCP2-DNA association is therefore vital to better understand its function and connection to disease pathogenesis. CA repeats are repetitive microsatellite DNA elements distributed throughout the genome whose modifications may potentially constitute an epigenetic code with an as-yet-unknown function ([ 11 ][9]). In a search of CA repeat “readers,” Ibrahim et al. unexpectedly identified MeCP2 as a binder in biochemical assays. The authors subsequently found MeCP2 to be the only MBD family member to bind CA repeats. Using genome-wide chromatin and DNA immunoprecipitation sequencing (ChIP-seq and DIP-seq), Ibrahim et al. further discovered that MeCP2 also binds both methylated and hydroxymethylated CA repeats in fibroblast cells, with hydroxymethyl being the strongest target. This binding feature was overlooked for decades, probably because of their repetitive nature and because asymmetric modification of CA repeats require an unusually high sequencing coverage to be detected. By reanalyzing whole-genome bisulfite sequencing (WGBS) and ChIP-seq data in neuronal cells and in the mouse brain, the authors found strong MeCP2-enrichment on modified cytosines within CA repeats, implying a physiological relevance of this interaction in the brain. ![Figure][10] A new binding motif for MeCP2 MeCP2 binds to methylated or hydroxymethylated cytosine within cytosine-adenine (CA) repeats in addition to its known binding sites. A Rett syndrome-causing MECP2 mutation, R133C, disrupts the MeCP2 binding to hydroxymethylated CA repeats. This leads to more condensed nucleosomes both within and flanking the CA repeats within lamina-associated domains (LADs); however, outside LADs, the nucleosomes are more condensed only within CA repeats. GRAPHIC: V. ALTOUNIAN/ SCIENCE Although MeCP2 has been described as a transcriptional repressor, growing evidence suggests that it also organizes three-dimensional (3D) chromatin architecture. High-resolution imaging and electron microscopy reveal that changes in MeCP2 abundance substantially alters heterochromatin structure and compaction in neurons ([ 12 ][11], [ 13 ][12]). The study of Ibrahim et al. is consistent with MeCP2's role in chromatin organization because they demonstrated a new function of MeCP2 as a long-range nucleosome organizer. The absence of MeCP2 resulted in an intriguing dual effect in a chromatin context-dependent manner. Within lamina-associated domains (LADs), the nucleosome density is increased both within and around CA repeats. By contrast, outside the LADs, the nucleosome density is increased within CA repeats but decreased around them. LADs are chromatin domains associated with the nuclear lamina (area at the inner face of the nuclear membrane) that harbor hundreds of genes that are mostly transcriptionally inhibited (∼5 to 10% are highly expressed). Therefore, the presence of MeCP2 results in more “open” chromatin that favors gene activation inside LADs and more “closed” chromatin around CA repeats, which tends to inhibit gene expression outside LADs (see the figure). This observation raises an interesting possibility that in addition to linear sequence features and modifications, the 3D subnuclear localization of MeCP2 binding sites also contributes to chromatin remodeling and gene expression changes. In line with this notion, Ibrahim et al. found that among the genes dysregulated in fibroblasts upon MeCP2 loss, expression of the majority is down-regulated in LADs. Ibrahim et al. further crystalized the MeCP2 MBD in contact with hydroxymethylated CA repeat DNA and identified R133 as the residue that recognizes the hydroxymethyl group through direct interaction. The RTT-causing mutation R133C severely impaired this interaction, suggesting that binding to these repeats may be relevant to RTT pathogenesis. Human mutations have been extremely helpful in pinpointing the contributions of MeCP2 protein domains to RTT pathogenesis. Mutations in the MBD that abolish mCG and mCH binding cause severe patient phenotypes similar to complete loss of the gene (null), whereas other RTT-causing mutations that disrupt the transcriptional repression domain, such as R306C and R273X (where X represents a truncating mutation), do not reproduce the severe null phenotype ([ 6 ][5], [ 14 ][13]). Similarly, R133C has a milder effect than other MBD mutations ([ 6 ][5], [ 15 ][14]), probably because this mutant still binds to methylated CA repeats, which may constitute ∼80% of all modified CA repeats in neurons. The loss of MeCP2 binding to hydroxymethylated CA repeats could be one of the many factors that contribute to RTT pathogenesis. It will be important to determine the true abundance and genomic distribution of methylated and hydroxymethylated CA repeats, as well as the proportion of these DNA elements bound by MeCP2 in neurons. Also, the molecular basis of nucleosome density alteration inside and outside LADs upon MeCP2 loss is unclear. And it will be interesting to determine the effects of MeCP2 binding to modified CA repeats on gene expression within or outside LADs in the brain. The discovery that MeCP2 binds a new CA repeat motif that may influence chromatin structure in specific LAD contexts provides opportunities to investigate the consequence of this binding on maintaining healthy brain function. 1. [↵][15]1. R. E. Amir et al ., Nat. Genet. 23, 185 (1999). [OpenUrl][16][CrossRef][17][PubMed][18][Web of Science][19] 2. [↵][20]1. J. D. Lewis et al ., Cell 69, 905 (1992). [OpenUrl][21][CrossRef][22][PubMed][23][Web of Science][24] 3. [↵][25]1. A. Ibrahim et al ., Science 372, eabd5581 (2021). 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/334117
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Jian Zhou,Huda Zoghbi. Repeat after Me(CP2)![J]. Science,2021.
APA	Jian Zhou,&Huda Zoghbi.(2021).Repeat after Me(CP2)!.Science.
MLA	Jian Zhou,et al."Repeat after Me(CP2)!".Science (2021).