Biology subjects

Lastuvkova, A.

Publications and source records attributed to Lastuvkova, A..

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↗

bioRxiv2021

Distinct roles for CDK-Mediator in controlling Polycomb-dependent chromosomal interactions and priming genes for induction

Precise control of gene expression underpins normal development. This relies on mechanisms that enable communication between gene promoters and other regulatory elements. In embryonic stem cells (ESCs), the CDK-Mediator (CDK-MED) complex has been reported to physically link gene regulatory elements to enable gene expression and also prime genes for induction during differentiation. Here we discover that CDK-MED contributes little to 3D genome organisation in ESCs, but has a specific and essential role in controlling interactions between inactive gene regulatory elements bound by Polycomb repressive complexes (PRCs). These interactions are established by the canonical PRC1 (cPRC1) complex but rely on CDK-MED, which facilitates binding of cPRC1 to its target sites. Importantly, through separation of function experiments, we reveal that this collaboration between CDK-MED and cPRC1 in creating long-range interactions does not function to prime genes for induction during differentiation. Instead, we discover that priming relies on an interaction-independent mechanism whereby the CDK module supports core Mediator engagement with gene promoters to enable gene activation.

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↗