Integrating transcription and splicing into cell fate: Transcription factors on the block

Boumpas, Panagiotis; Merabet, Samir; Carnesecchi, Julie

doi:10.1002/wrna.1752

Cited by 10 publications

(13 citation statements)

References 166 publications

(270 reference statements)

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“…During early development, TFs and RBPs deposited by the mother into the embryo shape early embryonic milestones across metazoans 13, 14 . Initially, cell number increases, followed by differentiation into specific cell types, which is driven by transcription and co-transcriptional splicing 3, 15 . However, the mechanisms by which maternally deposited TFs and RBPs function together to drive the process of co-transcriptional splicing in a sex-specific manner remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Sex-specific transcript diversity is regulated by a maternal transcription factor in earlyDrosophilaembryos

Ray

Conard

Urban

et al. 2021

Preprint

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Maternally deposited RNAs and proteins play a crucial role in initiating zygotic transcription during early embryonic development. However, the mechanisms by which maternal factors regulate zygotic transcript diversity early in development remain poorly understood. Furthermore, how early in development sex-specific transcript diversity occurs is not known genome-wide in any organism. Here, we determine that sex-specific transcript diversity occurs much earlier in development than previously thought in Drosophila, concurrent with Zygotic genome activation (ZGA). We use genetic, biochemical, and genomic approaches to demonstrate that the essential maternally-deposited pioneer factor CLAMP (Chromatin linked adapter for MSL proteins) is a key regulator of sex-specific transcript diversity in the early embryo via the following mechanisms: 1) In both sexes, CLAMP directly binds to the gene bodies of female and male sex-specifically spliced genes. 2) In females, CLAMP modulates chromatin accessibility of an alternatively-spliced exon within Sex-lethal, the master regulator of sex determination, to promote protein production. 3) In males, CLAMP regulates Maleless (MLE) distribution, a spliceosome component to prevent aberrant sex-specific splicing. Thus, we demonstrate for the first time how a maternal factor regulates early zygotic transcriptome diversity sex-specifically. We also developed a new tool to measure how splicing changes over time called time2splice.

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Section: Introductionmentioning

confidence: 99%

Sex-specific transcript diversity is regulated by a maternal transcription factor in earlyDrosophilaembryos

Ray

Conard

Urban

et al. 2021

Preprint

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“…Chromatin-bound transcription factors (TFs) and RNA binding proteins (RBPs) cotranscriptionally regulate alternative splicing [1][2][3][4] . However, the mechanisms by which TFs and RBPs coordinate transcription and alternative splicing at specific genomic locations in a 2 particular cell type to drive specific alternative splicing events remain poorly understood.…”

Section: Main Text (1500 Words)mentioning

confidence: 99%

“…Mechanisms to drive precise alternative splicing at thousands of genomic loci, which establish sex and cell type-specific transcriptome diversity, remain important targets for biological understanding because they establish sex and cell type-specific transcriptome diversity. Chromatin-bound transcription factors (TFs) and RNA binding proteins (RBPs) co-transcriptionally regulate alternative splicing 1–4 . However, the mechanisms by which TFs and RBPs coordinate transcription and alternative splicing at specific genomic locations in a particular cell type to drive specific alternative splicing events remain poorly understood.…”

Section: Main Textmentioning

confidence: 99%

Dual DNA/RNA-binding factor regulates dynamics of hnRNP splicing condensates

Ray,

Zaborowsky,

Mahableshwarkar

et al. 2024

Preprint

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Despite decades of research, mechanisms by which co-transcriptional alternative splicing events are targeted to the correct genomic locations to drive cell fate decisions remain unknown. By combining structural and molecular approaches, we define a new mechanism by which an essential transcription factor (TF) targets co-transcriptional splicing through physical and functional interaction with RNA and RNA binding proteins (RBPs). We show that an essential TF co-transcriptionally regulates sex-specific alternative splicing by directly interacting with a subset of target RNAs on chromatin and modulating the dynamics of hnRNPA2 homolog nuclear splicing condensates.

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“…Transcription and RNA processing are increasingly understood to be coupled events (Boumpas et al, 2022; Brody et al, 2011; Brody & Shav‐Tal, 2011; Kornblihtt, 2006; Kornblihtt et al, 2004; Neugebauer, 2019; Tellier et al, 2020). Co‐transcriptional splicing is estimated to occur at least ~80% of the time with many mRNAs maintaining their localization at the site of transcription while undergoing processing (Brody et al, 2011; Neugebauer, 2019; Rambout & Maquat, 2020).…”

Section: Hmgbs Interactions With Rna Impact Hmgb Cell Biologymentioning

confidence: 99%

The DNA binding high mobility group box protein family functionally binds RNA

et al. 2023

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Nucleic acid binding proteins regulate transcription, splicing, RNA stability, RNA localization, and translation, together tailoring gene expression in response to stimuli. Upon discovery, these proteins are typically classified as either DNA or RNA binding as defined by their in vivo functions; however, recent evidence suggests dual DNA and RNA binding by many of these proteins. High mobility group box (HMGB) proteins have a DNA binding HMGB domain, act as transcription factors and chromatin remodeling proteins, and are increasingly understood to interact with RNA as means to regulate gene expression. Herein, multiple layers of evidence that the HMGB family are dual DNA and RNA binding proteins is comprehensively reviewed. For example, HMGB proteins directly interact with RNA in vitro and in vivo, are localized to RNP granules involved in RNA processing, and their protein interactors are enriched in RNA binding proteins involved in RNA metabolism. Importantly, in cell‐based systems, HMGB–RNA interactions facilitate protein–protein interactions, impact splicing outcomes, and modify HMGB protein genomic or cellular localization. Misregulation of these HMGB–RNA interactions are also likely involved in human disease. This review brings to light that as a family, HMGB proteins are likely to bind RNA which is essential to HMGB protein biology.This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein‐RNA Recognition RNA Interactions with Proteins and Other Molecules > RNA‐Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications

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Integrating transcription and splicing into cell fate: Transcription factors on the block

Cited by 10 publications

References 166 publications

Sex-specific transcript diversity is regulated by a maternal transcription factor in earlyDrosophilaembryos

Sex-specific transcript diversity is regulated by a maternal transcription factor in earlyDrosophilaembryos

Dual DNA/RNA-binding factor regulates dynamics of hnRNP splicing condensates

The DNA binding high mobility group box protein family functionally binds RNA

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