MeCP2 and Major Satellite Forward RNA Cooperate for Pericentric Heterochromatin Organization

Fioriniello, Salvatore; Csukonyi, Eva; Marano, Domenico; Brancaccio, Arianna; Madonna, Michele; Zarrillo, Carmela; Romano, Alessia; Marracino, Federico; Matarazzo, Maria R.; D’Esposito, Maurizio; Ragione, Floriana Della

doi:10.1016/j.stemcr.2020.11.006

Cited by 16 publications

(19 citation statements)

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“…HSATII RNA is also aberrantly enriched in Parkinson's disease patient blood samples, and MeCP2 regulates pericentric heterochromatin regions in neurons in an RNA-dependent manner, suggesting a role for HSATII RNA with MeCP2 in intellectual disorders (Billingsley et al, 2019;Marano et al, 2019). A paper published during the preparation of this manuscript showed that MeCP2 and major satellite RNA cooperate to organize pericentric heterochromatin, and that RNA interaction depends on the TRD (Fioriniello et al, 2020). This is consistent with the presence of an RBD overlapping MeCP2's NID, as mentioned earlier.…”

Section: Lncrna Interactionsmentioning

confidence: 89%

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

2021

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Mutations in methyl CpG binding protein 2 (MeCP2) are the major cause of Rett syndrome (RTT), a rare neurodevelopmental disorder with a notable period of developmental regression following apparently normal initial development. Such MeCP2 alterations often result in changes to DNA binding and chromatin clustering ability, and in the stability of this protein. Among other functions, MeCP2 binds to methylated genomic DNA, which represents an important epigenetic mark with broad physiological implications, including neuronal development. In this review, we will summarize the genetic foundations behind RTT, and the variable degrees of protein stability exhibited by MeCP2 and its mutated versions. Also, past and emerging relationships that MeCP2 has with mRNA splicing, miRNA processing, and other non-coding RNAs (ncRNA) will be explored, and we suggest that these molecules could be missing links in understanding the epigenetic consequences incurred from genetic ablation of this important chromatin modifier. Importantly, although MeCP2 is highly expressed in the brain, where it has been most extensively studied, the role of this protein and its alterations in other tissues cannot be ignored and will also be discussed. Finally, the additional complexity to RTT pathology introduced by structural and functional implications of the two MeCP2 isoforms (MeCP2-E1 and MeCP2-E2) will be described. Epigenetic therapeutics are gaining clinical popularity, yet treatment for Rett syndrome is more complicated than would be anticipated for a purely epigenetic disorder, which should be taken into account in future clinical contexts.

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Section: Lncrna Interactionsmentioning

confidence: 89%

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

2021

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“…MeCP2 interacts with more than 40 binding partners, including transcriptional regulators, chromatin modifiers and RNA- splicing factors [ 231 ]. MeCP2 chromatin binding is controlled by m 5 C, and recent studies show enrichment of MeCP2 on long non-coding RNAs (lncRNAs), such as retinal noncoding RNA3 (RNCR3) [ 232 ], muscle-specific long non-coding RNA (ChRO1) [ 233 ], and major Satellite Forward RNAs [ 234 ]. This MeCP2 enrichment on lncRNAs promotes deposition of H3K9me3 and H4K20me3 and heterochromatin formation.…”

Section: Fine-tuning Chromatin and Transcription Through Rna Modifications And Rna-modifying Proteinsmentioning

confidence: 99%

RNA Epigenetics: Fine-Tuning Chromatin Plasticity and Transcriptional Regulation, and the Implications in Human Diseases

Willbanks

Wood

Cheng

2021

Genes

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Chromatin structure plays an essential role in eukaryotic gene expression and cell identity. Traditionally, DNA and histone modifications have been the focus of chromatin regulation; however, recent molecular and imaging studies have revealed an intimate connection between RNA epigenetics and chromatin structure. Accumulating evidence suggests that RNA serves as the interplay between chromatin and the transcription and splicing machineries within the cell. Additionally, epigenetic modifications of nascent RNAs fine-tune these interactions to regulate gene expression at the co- and post-transcriptional levels in normal cell development and human diseases. This review will provide an overview of recent advances in the emerging field of RNA epigenetics, specifically the role of RNA modifications and RNA modifying proteins in chromatin remodeling, transcription activation and RNA processing, as well as translational implications in human diseases.

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“…MeCP2 is one of the most abundant nuclear proteins in neurons, with a number of molecules approaching that of histone octamers [17]. Due to its high expression levels and its extensive genomic distribution, MeCP2 has been proposed to modulate the configuration of the neuronal epigenome through the recruitment of several molecular partners [17,30,56,57,59]. With this evidence in mind, it is not surprising that MeCP2 dysfunction leads to extensive epigenomic alterations in neurons, which include the uncontrolled spreading of histone modifications, the altered recruitment of enzymatic factors, and the aberrant binding of proteins involved in the regulation of gene expression (described hereafter).…”

Section: Mecp2: "The Guardian" Of Neuronal Epigenomementioning

confidence: 99%

“…The role of MeCP2 in the modulation of genome architecture and its ability to compact heterochromatin in neurons have been largely demonstrated, as well as the involvement of other proteins and ncRNAs that cooperate with MeCP2 in this process [30,[56][57][58][59][60]. It has long been known that in mouse cells, MeCP2 accumulates at pericentric heterochromatin (PCH) [15], a large fraction of constitutive heterochromatin containing hypermethylated major satellite repeats, which is organized in higher-order structures called chromocenters [57] (Figure 3A).…”

Section: Mecp2 Is a Genome-wide Modulator Of Chromatin Architecture In Neuronsmentioning

confidence: 99%

“…In addition, increased transcriptional noise has been observed in Mecp2-null neurons, thus underlining a role of MeCP2 in the repression of spurious transcription of repetitive elements [17]. Furthermore, MeCP2 is implicated in higher-order organization of pericentric heterochromatin, a considerable portion of the genome thought to form silent compartments in the nucleus [30,[56][57][58][59][60]. Conversely, MeCP2 seems to be dispensable for the formation of self-interacting genomic regions, such as topologically associating domains (TADs) [61].…”

Section: Introductionmentioning

confidence: 99%

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Transcriptomic and Epigenomic Landscape in Rett Syndrome

et al. 2021

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Rett syndrome (RTT) is an extremely invalidating, cureless, developmental disorder, and it is considered one of the leading causes of intellectual disability in female individuals. The vast majority of RTT cases are caused by de novo mutations in the X-linked Methyl-CpG binding protein 2 (MECP2) gene, which encodes a multifunctional reader of methylated DNA. MeCP2 is a master epigenetic modulator of gene expression, with a role in the organization of global chromatin architecture. Based on its interaction with multiple molecular partners and the diverse epigenetic scenario, MeCP2 triggers several downstream mechanisms, also influencing the epigenetic context, and thus leading to transcriptional activation or repression. In this frame, it is conceivable that defects in such a multifaceted factor as MeCP2 lead to large-scale alterations of the epigenome, ranging from an unbalanced deposition of epigenetic modifications to a transcriptional alteration of both protein-coding and non-coding genes, with critical consequences on multiple downstream biological processes. In this review, we provide an overview of the current knowledge concerning the transcriptomic and epigenomic alterations found in RTT patients and animal models.

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MeCP2 and Major Satellite Forward RNA Cooperate for Pericentric Heterochromatin Organization

Cited by 16 publications

References 44 publications

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

RNA Epigenetics: Fine-Tuning Chromatin Plasticity and Transcriptional Regulation, and the Implications in Human Diseases

Transcriptomic and Epigenomic Landscape in Rett Syndrome

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