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A germline PAF1 paralog complex ensures cell type-specific gene expression

ABSTRACT: Animal germline development and fertility rely on paralogs of general transcription factors that recruit RNA polymerase II to ensure cell type-specific gene expression. It remains unclear whether gene expression processes downstream of such paralog-based transcription is distinct from that of canonical RNA polymerase II genes. In Drosophila, the testis-specific TBP-associated factors (tTAFs) activate over a thousand spermatocyte-specific gene promoters to enable meiosis and germ cell differentiation. Here we show that efficient termination of tTAF-activated transcription requires a testis-specific Polymerase Associated Factor 1 Complex (tPAF) composed of paralogs of canonical Polymerase Associated Factor 1 Complex (PAF1C) proteins. Defective transcription termination in tPAF mutants causes aberrant expression of hundreds of downstream genes due to read-in transcription, compromising cell type-specific gene expression in spermatocytes. Consistently, tPAF is required for the segregation of meiotic chromosomes, sperm individualisation, and male fertility. Comparative in vivo proximity labeling assays of tPAF and PAF1C showed tPAF-specific association with tTAF as well as connections to central RNA polymerase II termination factors. Our study uncovers transcription termination as a developmentally regulated process required for cell type-specific gene expression.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE263955 | GEO | 2024/04/16

REPOSITORIES: GEO

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A germline PAF1 paralog complex ensures cell type-specific gene expression (co-IP data)

Project description:Animal germline development and fertility relies on paralogs of general transcription factors that recruit RNA polymerase II to ensure cell type-specific gene expression. It remains unclear whether gene expression processes downstream of such paralog-based transcription is distinct from that of canonical RNA polymerase II genes. In Drosophila, the testis-specific TBP-associated factors (tTAFs) activate over a thousand spermatocyte-specific gene promoters to enable meiosis and germ cell differentiation. Here we show that efficient termination of tTAF-activated transcription requires a testis-specific Polymerase Associated Factor 1 Complex (tPAF) composed of paralogs of canonical Polymerase Associated Factor 1 Complex (PAF1C) proteins. Defective transcription termination in tPAF mutants causes aberrant expression of hundreds of downstream genes due to read-in transcription, compromising cell type-specific gene expression in spermatocytes. Consistently, tPAF is required for the segregation of meiotic chromosomes, sperm individualisation, and male fertility. Comparative in vivo proximity labeling assays of tPAF and PAF1C showed tPAF-specific association with tTAF as well as connections to central RNA polymerase II termination factors. Our study uncovers transcription termination as a developmentally regulated process required for cell type-specific gene expression.

2024-04-13 | PXD049360 | Pride

A germline PAF1 paralog complex ensures cell type-specific gene expression (proximity labeling data)

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The PAF1 complex promotes 3‘ processing of pervasive transcripts [RNA-seq]

Project description:The PAF1 complex (PAF1C) functions in multiple transcriptional and co-transcriptional processes. Although many aspects of the requirement for PAF1 in coding gene transcription have been heavily studied, the function of PAF1C at sites of non-coding transcription is poorly understood. eRNAs and PROMPTs are pervasive transcripts transcribed by RNA Polymerase II and rapidly degraded after 3’ endonucleolytic cleavage by the Integrator complex (Integrator). Here we show that PAF1C depletion results in near universal 3’ end processing defects in pervasive transcripts, leading to transcription termination dysregulation. Mechanistically, PAF1C recruits Integrator to chromatin through direct interactions promoting timely cleavage and transcription termination of pervasive transcripts. We also show that PAF1C recruits Integrator to the promoters of coding genes, where PAF1C then dissociates from the Integrator complex upon entry into processive elongation. Our results demonstrate an unexpected function for PAF1C in limiting the length and accumulation of pervasive transcripts, while highlighting a general requirement for PAF1C in Integrator recruitment.

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The PAF1 complex promotes 3‘ processing of pervasive transcripts [3'-seq]

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Ubiquitin-dependent transfer of PAF1c from MYC onto RNA Polymerase controls double-strand break repair at active promoters

Project description:MYC family proteins are oncogenic transcription factors that can globally affect the function of RNA Polymerase II (RNAPII). The ability of MYC proteins to promote transcription elongation depends on their ubiquitination, but the underlying mechanism and its biological relevance are unknown. Here we show that MYC and the Polymerase II associated factor, PAF1c, interact directly and their function is mutually dependent, since the specific binding of MYC to active promoters depends on PAF1c and, conversely, PAF1c is required for MYC-dependent pause release. Upon binding, PAF1c is rapidly transferred from MYC onto RNAPII and this transfer is driven by the HUWE1 ubiquitin ligase. Both MYC and HUWE1 globally control histone H2B ubiquitylation, which promotes transcriptional elongation and alters chromatin structure for double-strand break repair. Consistently, MYC suppresses the accumulation of double-strand breaks at promoters in response to topoisomerase II inhibition. While depletion of PAF1c has only minor effects on MYC-dependent gene expression, MYC induces rampant transcription-dependent DNA damage in PAF1c-depleted cells. We propose that the HUWE1-dependent transfer of PAF1c from MYC onto RNAPII is critical for absorbing the topological stress accompanied with deregulated and oncogenic transcription.

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The Paf1 complex broadly impacts the transcriptome of Saccharomyces cerevisiae

Project description:The polymerase associated factor 1 complex (Paf1C) is a multifunctional epigenetic regulator of RNA polymerase II (Pol II) transcription. Paf1C controls gene expression by stimulating the placement of co-transcriptional histone modifications, influencing nucleosome occupancy in coding regions, facilitating transcription termination, and regulating nuclear export of RNAs. In this study, we investigate the extent to which these functions of Paf1C combine to influence the Saccharomyces cerevisiae transcriptome. Using conditions that enrich for unstable transcripts, we show that deletion of PAF1 affects all classes of Pol II-transcribed RNAs including multiple classes of noncoding transcripts. Gene ontology analysis revealed that mRNAs encoding genes involved in iron and phosphate homeostasis were differentially affected by deletion of PAF1. We further investigated these two groups of mRNAs with the goal of identifying overarching mechanisms of up and down-regulation in cells lacking Paf1. Our results indicate that only a subset of the observed changes result from loss of Paf1C-promoted histone modifications. We also found that transcription of the FET4 gene is differentially regulated by Paf1 and an upstream CUT. Together these data highlight the complexity of the epigenetic regulation of Pol II transcription imposed by Paf1C and identify a role for Paf1C in promoting CUT transcription.

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The PAF1 Complex Regulates Transcriptional Termination and Reinitiation [CUT&Tag]

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