RBM45 is an m6A-binding protein that affects neuronal differentiation and the splicing of a subset of mRNAs

Choi, Seung Hyuk; Flamand, Mathieu N.; Liu, Bei; Zhu, Huanyu; Hu, Meghan; Wang, Melanie; Sewell, Jonathon; Holley, Christopher L.; Al‐Hashimi, Hashim M.; Meyer, Kate D.

doi:10.1016/j.celrep.2022.111293

Cited by 23 publications

(9 citation statements)

References 62 publications

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“…For example, we found a motif corresponding to RBM45 in exon 12 of TPCN1 (Figure 4D, Table S4), which seems to promote exon inclusion. RBM45 regulates constitutive splicing and can probably activate or repress the inclusion of an exon, but the exact mechanisms are currently unknown 58 . Taken together, characterizing important sequence features from DL models can identify splicing regulators beyond those we can identify based on available RBP measurements.…”

Section: Resultsmentioning

confidence: 99%

Predicting cell-type-specific exon inclusion in the human brain reveals more complex splicing mechanisms in neurons than glia

Michielsen,

Hsu,

Joglekar

et al. 2024

Preprint

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Alternative splicing contributes to molecular diversity across brain cell types. RNA-binding proteins (RBPs) regulate splicing, but the genome-wide mechanisms remain poorly understood. Here, we used RBP binding sites and/or the genomic sequence to predict exon inclusion in neurons and glia as measured by long-read single-cell data in human hippocampus and frontal cortex. We found that alternative splicing is harder to predict in neurons compared to glia in both brain regions. Comparing neurons and glia, the position of RBP binding sites in alternatively spliced exons in neurons differ more from non-variable exons indicating distinct splicing mechanisms. Model interpretation pinpointed RBPs, including QKI, potentially regulating alternative splicing between neurons and glia. Finally, using our models, we accurately predict and prioritize the effect of splicing QTLs. Taken together, our models provide new insights into the mechanisms regulating cell-type-specific alternative splicing and can accurately predict the effect of genetic variants on splicing.

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Section: Resultsmentioning

confidence: 99%

Predicting cell-type-specific exon inclusion in the human brain reveals more complex splicing mechanisms in neurons than glia

Michielsen,

Hsu,

Joglekar

et al. 2024

Preprint

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“…Among these modifiers, the most widely studied is m6A, which is particularly abundant in the brain and is essential for neurodevelopment. Recent studies have shown that the m6A binding protein RBM45 is required for NB cell differentiation [ 29 ], and in cancer stem cells generated from glioblastoma patients, PDGFR (platelet-derived growth factor receptor) activity exhibits enhanced m6A methylation, which encourages cell maintenance through control of mitophagy [ 30 ]. This evidence further reinforces the importance of posttranscriptional RNA modifications in cancer progression, but it remains unclear whether there is an impact on tumours through the methylation of KCNH2.…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis of the voltage-gated potassium channel-associated gene KCNH2 across cancers

Zheng

Song

2023

BMC Bioinformatics

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KCNH2 encodes the human ether-a-go-go-related gene (hERG) potassium channel and is an important repolarization reserve for regulating cardiac electrical activity. Increasing evidence suggests that it is involved in the development of various tumours, yet a thorough analysis of the underlying process has not been performed. Here, we have comprehensively examined the role of KCNH2 in multiple cancers by assessing KCNH2 gene expression, diagnostic and prognostic value, genetic alterations, immune infiltration correlations, RNA modifications, mutations, clinical correlations, interacting proteins, and associated signalling pathways. KCNH2 is differentially expressed in over 30 cancers and has a high diagnostic value for 10 tumours. Survival analysis showed that high expression of KCNH2 was associated with a poor prognosis in glioblastoma multiforme (GBM) and hepatocellular carcinoma (LIHC). Mutations and RNA methylation modifications (especially m6A) of KCNH2 are associated with its expression in multiple tumours. KCNH2 expression is correlated with tumour mutation burden, microsatellite instability, neoantigen load, and mutant-allele tumour heterogeneity. In addition, KCNH2 expression is associated with the tumour immune microenvironment and its immunosuppressive phenotype. KEGG signalling pathway enrichment analysis revealed that KCNH2 and its interacting molecules are involved in a variety of pathways related to carcinogenesis and signal regulation, such as the PI3K/Akt and focal adhesion pathways. Overall, we found that KCNH2 and its interaction molecular are expected to be immune-related biomarkers for cancer diagnosis and prognosis evaluation, and are potential regulatory targets of singalling pathways for tumour development due to their significant role in cancers.

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“…The fragile X messenger ribonucleoprotein (FMRP) has been shown to preferentially bind methylated transcripts and facilitate their nuclear export ( Edens et al, 2019 ). Additionally, our group identified RBM45 as a brain-enriched m 6 A reader protein that can impact splicing and regulate neuronal differentiation ( Choi et al, 2022 ).…”

Section: A Function and Regulation In The Brainmentioning

confidence: 99%

Studying m6A in the brain: a perspective on current methods, challenges, and future directions

Tegowski,

Meyer

2024

Front. Mol. Neurosci.

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A major mechanism of post-transcriptional RNA regulation in cells is the addition of chemical modifications to RNA nucleosides, which contributes to nearly every aspect of the RNA life cycle. N6-methyladenosine (m6A) is a highly prevalent modification in cellular mRNAs and non-coding RNAs, and it plays important roles in the control of gene expression and cellular function. Within the brain, proper regulation of m6A is critical for neurodevelopment, learning and memory, and the response to injury, and m6A dysregulation has been implicated in a variety of neurological disorders. Thus, understanding m6A and how it is regulated in the brain is important for uncovering its roles in brain function and potentially identifying novel therapeutic pathways for human disease. Much of our knowledge of m6A has been driven by technical advances in the ability to map and quantify m6A sites. Here, we review current technologies for characterizing m6A and highlight emerging methods. We discuss the advantages and limitations of current tools as well as major challenges going forward, and we provide our perspective on how continued developments in this area can propel our understanding of m6A in the brain and its role in brain disease.

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RBM45 is an m6A-binding protein that affects neuronal differentiation and the splicing of a subset of mRNAs

Cited by 23 publications

References 62 publications

Predicting cell-type-specific exon inclusion in the human brain reveals more complex splicing mechanisms in neurons than glia

Predicting cell-type-specific exon inclusion in the human brain reveals more complex splicing mechanisms in neurons than glia

Integrated analysis of the voltage-gated potassium channel-associated gene KCNH2 across cancers

Studying m6A in the brain: a perspective on current methods, challenges, and future directions

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