MBD5, a m5C RNA reader, regulates histone ubiquitylation in development and function
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA923391 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23071957.fastq.gz | Fastqsanger.gz | |||
| SRR23071958.fastq.gz | Fastqsanger.gz | |||
| SRR23071959.fastq.gz | Fastqsanger.gz | |||
| SRR23071960.fastq.gz | Fastqsanger.gz | |||
| SRR23071961.fastq.gz | Fastqsanger.gz |
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Project description:Methyl-CpG-binding domain (MBD)-containing proteins are readers of epigenetic information. The founding member, MeCP2, mutated in the Rett Syndrome, binds to methylated CpG DNAs. MBD5 is an evolutionarily conserved MBD family member associated with epilepsy, autism spectrum disorders (ASD), and early onset dementia. The mechanism of action of MBD5 remains unclear. Here we report that mbd5 regulates embryonic development, erythrocyte differentiation, iron metabolism, and behavior in zebrafish. MBD5 is essential to activate the expression of erythrocyte differentiation genes (e.g., hbae3), iron-regulated genes (e.g., fth1), and ASD-related genes (e.g., gabbr2), by binding to 5-methylcytosine (m5C) modified mRNAs, interacting with and stabilizing Additional Sex Combs Like 1 (ASXL1), a component of the Polycomb Repressive Deubiquinase (PR-DUB) complex, to facilitate removal of the repressive monoubiquitin mark at histone H2A (H2A-K119Ub), thereby facilitating gene activation. Together, these findings reveal MBD5 as a m5C RNA reader that links RNA methylation to histone modification in vivo.
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Project description:To address how Mbd5 binding to m5C RNAs mediates transcriptional activation of its target genes. Using the Tg[zhsp70l:FLAGmbd5iso2-E2AGFP] zebrafish, we performed heat shock at multiple developmental stages and carried out co-immunoprecipitation (co-IP) at 4 dpf using the FLAG antibody, followed by mass spectrometry
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Project description:A common mRNA modification is 5-methylcytosine (m5C), whose role in gene-transcript processing and cancer remains unclear. Here we identify Serine/arginine-Rich Splicing Factor 2 (SRSF2) as a reader of m5C, and impaired SRSF2 m5C binding as a potential contributor to leukemogenesis. Structurally, we identify residues involved in m5C recognition and in the impact of the prevalent leukemia-associated mutation SRSF2P95H. We show that SRSF2 binding and m5C colocalize within transcripts. Furthermore, knocking down the m5C writer NSUN2 decreases mRNA m5C, reduces SRSF2 binding, and alters RNA splicing. We also show that the SRSF2P95H mutation impairs the ability of the protein to read m5C-marked mRNA, notably reducing its binding to key leukemia-related transcripts in leukemic cells. In leukemia patients, low NSUN2 expression leads to mRNA m5C hypomethylation and, combined with SRSF2P95H, predicts poor outcomes. Altogether, we highlight an unrecognized mechanistic link between epitranscriptomics and a key oncogenesis driver.
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Project description:We discovered the YBX1 in the lipid-induced particles assembled by DDX49, YBX1 is an m5C reader and constitutively associates with Timp2 mRNA in hepatocytes, we examined whether their association was dependent on the m5C modification of Timp2 mRNA, then we performed m5C-MeRIP-seq.
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Project description:The reversible epitranscriptomic mark, 5-methylcytosine (m5C) modification, is implicated in numerous cellular processes, but its role in neuronal development remains largely unexplored. In this study, we discovered high expression of the m5C reader Ybx1 in the developing mouse cortex. To elucidate its role in cortical development, Ybx1 was deleted in mouse embryonic cortical neural stem cells (NSCs). Interestingly, the deletion of Ybx1 led to perinatal mortality in mice, along with abnormal cortical development. Cortical progenitor cells lacking Ybx1 exhibited impaired proliferation and differentiation. Multi-omics analysis identified the target mRNAs of Ybx1, which encode the key cell cycle regulatory proteins, such as cyclin D2 (Ccnd2). Ybx1 was found to regulate the stability of its target transcripts. Both knockdown and overexpression of Ybx1 targets via in utero electroporation confirmed that they mediated the Ybx1 regulation of proliferation and differentiation of neural precursor cells. Further mechanistic analysis showed that deletion of Ybx1 resulted in the blocking of G1 to S phase transition in the cortical progenitor cells. This study highlights the crucial function of the m5C reader protein Ybx1 in promoting cell cycle progression of the embryonic cortical progenitors, essential for proper cortical development.
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Project description:The reversible epitranscriptomic mark, 5-methylcytosine (m5C) modification, is implicated in numerous cellular processes, but its role in neuronal development remains largely unexplored. In this study, we discovered high expression of the m5C reader Ybx1 in the developing mouse cortex. To elucidate its role in cortical development, Ybx1 was deleted in mouse embryonic cortical neural stem cells (NSCs). Interestingly, the deletion of Ybx1 led to perinatal mortality in mice, along with abnormal cortical development. Cortical progenitor cells lacking Ybx1 exhibited impaired proliferation and differentiation. Multi-omics analysis identified the target mRNAs of Ybx1, which encode the key cell cycle regulatory proteins, such as cyclin D2 (Ccnd2). Ybx1 was found to regulate the stability of its target transcripts. Both knockdown and overexpression of Ybx1 targets via in utero electroporation confirmed that they mediated the Ybx1 regulation of proliferation and differentiation of neural precursor cells. Further mechanistic analysis showed that deletion of Ybx1 resulted in the blocking of G1 to S phase transition in the cortical progenitor cells. This study highlights the crucial function of the m5C reader protein Ybx1 in promoting cell cycle progression of the embryonic cortical progenitors, essential for proper cortical development.
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Project description:The reversible epitranscriptomic mark, 5-methylcytosine (m5C) modification, is implicated in numerous cellular processes, but its role in neuronal development remains largely unexplored. In this study, we discovered high expression of the m5C reader Ybx1 in the developing mouse cortex. To elucidate its role in cortical development, Ybx1 was deleted in mouse embryonic cortical neural stem cells (NSCs). Interestingly, the deletion of Ybx1 led to perinatal mortality in mice, along with abnormal cortical development. Cortical progenitor cells lacking Ybx1 exhibited impaired proliferation and differentiation. Multi-omics analysis identified the target mRNAs of Ybx1, which encode the key cell cycle regulatory proteins, such as cyclin D2 (Ccnd2). Ybx1 was found to regulate the stability of its target transcripts. Both knockdown and overexpression of Ybx1 targets via in utero electroporation confirmed that they mediated the Ybx1 regulation of proliferation and differentiation of neural precursor cells. Further mechanistic analysis showed that deletion of Ybx1 resulted in the blocking of G1 to S phase transition in the cortical progenitor cells. This study highlights the crucial function of the m5C reader protein Ybx1 in promoting cell cycle progression of the embryonic cortical progenitors, essential for proper cortical development.
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Project description:The reversible epitranscriptomic mark, 5-methylcytosine (m5C) modification, is implicated in numerous cellular processes, but its role in neuronal development remains largely unexplored. In this study, we discovered high expression of the m5C reader Ybx1 in the developing mouse cortex. To elucidate its role in cortical development, Ybx1 was deleted in mouse embryonic cortical neural stem cells (NSCs). Interestingly, the deletion of Ybx1 led to perinatal mortality in mice, along with abnormal cortical development. Cortical progenitor cells lacking Ybx1 exhibited impaired proliferation and differentiation. Multi-omics analysis identified the target mRNAs of Ybx1, which encode the key cell cycle regulatory proteins, such as cyclin D2 (Ccnd2). Ybx1 was found to regulate the stability of its target transcripts. Both knockdown and overexpression of Ybx1 targets via in utero electroporation confirmed that they mediated the Ybx1 regulation of proliferation and differentiation of neural precursor cells. Further mechanistic analysis showed that deletion of Ybx1 resulted in the blocking of G1 to S phase transition in the cortical progenitor cells. This study highlights the crucial function of the m5C reader protein Ybx1 in promoting cell cycle progression of the embryonic cortical progenitors, essential for proper cortical development.
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Project description:RNA m5C methylation profile of MCF10A and MDA486 by using MeRIP-Seq protocol Immunoprecipitation of Methylated mRNA at Cytosine (m5C) residues: Affinity purified of anti-methyl cytosine (m5C) polyclonal antibody 7ug (Zymo Research, Catalog#A3001-50) was conjugated with protein-A magnetic beads for 2 h at 4°C in end to end rotator. After that, conjugated beads were extensively washed with RNA immunoprecipitation (RIP) wash buffer to remove unbound antibody. Fragmented 25 ug polyA RNA (mRNA) was incubated with m5C conjugated beads for overnight at 4°C in in the rotating platform in RIP buffer. RIP was done using Megna RNA Immunoprecipitation kit (Millipore, Catalog#17-700). m5C mRNA-immune bead complex was treated with proteinase K buffer to release m5C mRNA from the conjugated antibody. To isolate m5C, mRNA was treated with phenol:chloroform:isoamyl and mixed with 400 ul of chloroform, which was centrifuged at 14000 rpm for 10 minutes to separate aqueous phase. The aqueous phase was ethanol precipitated at -80°C for overnight, to get m5C mRNA. This precipitated m5C mRNA pellet was washed twice with 70% ethanol and air dried. Finally, m5C mRNA pellet was dissolved in nuclease free Water. The m5C mRNA integrity and conentration was quantified by bioanalyzer (Agilent) and Qubit 2.0 flurometer (Invitrogen). The fragmented mRNA was used by following TruSeq RNA Sample Preparation Guide to develop RNA-Seq library for sequencing.
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