Award details

Deciphering a novel interplay between RNA and chromatin

Reference	BB/X007820/1
Principal Investigator / Supervisor	Dr Faraz Mardakheh
Co-Investigators / Co-Supervisors	Dr Paola Scaffidi
Institution	Queen Mary University of London
Department	Barts Cancer Institute
Funding type	Research
Value (£)	634,167
Status	Current
Type	Research Grant
Start date	01/04/2023
End date	30/09/2026
Duration	42 months

Abstract

It is well-known that many signalling pathways control gene expression through modulating chromatin. However, the molecular mechanisms that regulate different aspects of chromatin structure and function in response to distinct signalling inputs are poorly characterised. A key group of chromatin regulators are the linker histone (H1) family of proteins, which promote chromatin condensation by interacting with the linker DNA regions that connect nucleosomes. Histone H1 binding to linker DNA leads to direct compaction of chromatin, as well as indirectly promoting heterochromatin formation by impairing the access of chromatin modulators to nucleosomes. Previous studies have revealed a pivotal role for histone H1 in controlling diverse aspects of cell behaviour, from regulation of gene expression to DNA replication and mitosis. However, the mechanisms that modulate histone H1 activity in response to distinct signalling inputs have remained largely unknown. Exciting preliminary results from our laboratory have revealed that upon activation of RAS-MAPK signalling, a pivotal signal transduction pathway that controls key cellular decisions such as cell-proliferation and differentiation, histone H1 directly binds to RNA. Using a state-of-art multi-disciplinary approach, we now aim to characterise this novel function of histone H1 in detail, defining the molecular mechanisms that control the RNA-binding activity of H1, the identity and regulation of its target RNAs, as well as the functional consequence of this association on chromatin biology, transcriptional and post-transcriptional regulation of gene expression, and cell-cycle progression.

Summary

Each cell in our body contains the same genetic information, yet this information is decoded in vastly different manners, allowing different cells to acquire distinct roles, which are together needed for the proper functioning of our tissues and organs. The genetic information is stored in DNA molecules, which reside in a part of the cell called the nucleus. In the nucleus, DNA is wrapped around a group of specialised proteins called histones, forming a DNA-protein structure known as chromatin. This protects the DNA from damage, and regulates access to the genetic information, which is crucial for determining which genes can be decoded at any given time. The packaging of chromatin therefore needs to be accurately controlled at all times, but it is not fully clear exactly his this is achieved in our cells. Our preliminary results have revealed that an important chromatin protein named histone H1 can also bind to RNA molecules. RNA molecules are intermediate molecules which mediate the decoding of genetic information from DNA, but recent findings suggest they can also control chromatin. Our aim now is to understand how histone H1 binds to RNA, and how this binding affects the decoding of genetic information and the structure of chromatin. To do this, we will use a variety of cutting-edge approaches to investigate how histone H1 interaction with RNA is regulated in cells. We will then reveal the impact of histone H1 binding to RNA on the decoding of genetic information. Finally, we will assess how changes in histone H1 function can control different cell behaviours such as cell-division. Addressing these fundamental questions will greatly advance our understanding of chromatin biology and its regulation, opening up new opportunities for modulating chromatin function in biotechnology (e.g. cell reprogramming) and medicine (new therapeutic targets).

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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