Biology subjects

Turberfield, A. H.

Publications and source records attributed to Turberfield, A. H..

3 recordsLinked to original sources

bioRxiv2022

A CpG island-encoded mechanism protects genes from premature transcription termination

Transcription must be highly controlled to regulate gene expression and development. However, our understanding of the molecular mechanisms that influence transcription and how these are coordinated in cells to ensure normal gene expression remains rudimentary. Here, we reveal that actively transcribed CpG island-associated gene promoters recruit SET1 chromatin modifying complexes to enable gene expression. Counterintuitively, this effect is independent of SET1 complex histone modifying activity, and instead relies on the capacity of these complexes to interact with the RNA Polymerase II-binding protein, WDR82. Unexpectedly, we discover that SET1 complexes sustain gene transcription by counteracting the activity of the ZC3H4/WDR82 protein complex, which we show can pervasively terminate both genic and extragenic transcription. Therefore, we discover a new gene regulatory mechanism whereby CpG island elements nucleate a protein complex that protects genic transcription from premature termination, effectively distinguishing genic from non-genic transcription to enable gene expression.

molecular biology↗

bioRxiv2020

BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome

Histone-modifying systems play fundamental roles in gene regulation and the development of multicellular organisms. Histone modifications that are enriched at gene regulatory elements have been heavily studied, but the function of modifications that are found more broadly throughout the genome remains poorly understood. This is exemplified by histone H2A mono-ubiquitylation (H2AK119ub1) which is enriched at Polycomb-repressed gene promoters, but also covers the genome at lower levels. Here, using inducible genetic perturbations and quantitative genomics, we discover that the BAP1 deubiquitylase plays an essential role in constraining H2AK119ub1 throughout the genome. Removal of BAP1 leads to pervasive accumulation of H2AK119ub1, which causes widespread reductions in gene expression. We show that elevated H2AK119ub1 represses gene expression by counteracting transcription initiation from gene regulatory elements, causing reductions in transcription-associated histone modifications. Furthermore, failure to constrain pervasive H2AK119ub1 compromises Polycomb complex occupancy at a subset of Polycomb target genes leading to their derepression, therefore explaining the original genetic characterisation of BAP1 as a Polycomb group gene. Together, these observations reveal that the transcriptional potential of the genome can be modulated by regulating the levels of a pervasive histone modification, without the need for elaborate gene-specific targeting mechanisms.

molecular biology↗

bioRxiv2019

KDM2 proteins constrain transcription from CpG island gene promoters independently of their histone demethylase activity

CpG islands (CGI) are associated with the majority of mammalian gene promoters and function to recruit chromatin modifying enzymes. It has therefore been proposed that CGIs regulate gene expression through chromatin-based mechanisms, however in most cases this has not been directly tested. Here, we reveal that the histone H3 lysine 36 (H3K36) demethylase activity of the CGI-binding KDM2 proteins contributes only modestly to the H3K36me2-depleted state at CGI-associated gene promoters and is dispensable for normal gene expression. Instead, we discover that KDM2 proteins play a widespread and demethylase-independent role in constraining gene expression from CGI-associated gene promoters. We further show that KDM2 proteins shape RNA Polymerase II occupancy but not chromatin accessibility at CGI-associated promoters. Together this reveals a demethylase-independent role for KDM2 proteins in transcriptional repression and uncovers a new function for CGIs in constraining gene expression.

molecular biology↗