Unveiling the Secrets of Intrinsically Disordered Proteins in Gene Regulation

Background

In mechanistic biology, proteins are often viewed as well-structured molecules. However, many proteins deviate from this model. Flexible, unstructured domains, known as Intrinsically Disordered Regions (IDRs), are increasingly recognised as crucial biological regulators. Recent technological advancements and innovative techniques have significantly contributed to our understanding of IDR function. A great example is found in the nucleus, where IDRs frequently mediate the interactions and behaviours of transcription factors.

Our team studies Creb binding protein (CBP) and EP300 (p300), two essential epigenetic enzymes that regulate transcription by acetylating histones. CBP and p300 perform distinct functions in the nucleus, despite their structured domains being nearly identical. We recently showed how the nuclear behaviour of CBP could be regulated by different IDRs. Intriguingly, the sequence properties of these regulatory IDRs are very different between CBP and p300, suggesting that IDRs could form the basis for their different functions.

The challenge

You will ask how the distinct behaviours of CBP and p300 are derived from different properties of their IDRs. You will receive training in cutting-edge, multidisciplinary approaches, such as gene editing with CRISPR, protein engineering, advanced microscopy (e.g. FRAP and single molecule imaging in live cells), single molecule FRET and genome wide mapping of histone modifications.

Our Team

The project brings together cross-disciplinary approaches in a collaboration between the labs of Dan Bose, Tim Craggs and Alison Twelvetrees at the University of Sheffield. We are a tight-knit and supportive team, forming part of a vibrant and collaborative community which spans the Nucleic Acids Institute and Centre for Single Molecule Biology. Our students are encouraged and supported to attend national and international meetings and to participate in further training opportunities.

For more information, check out our group webpage (www.bose-lab.org) or contact us (d.bose@sheffield.ac.uk).