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Overview

Eukaryotic transcriptional control is a complex process involving multiple cis-acting DNA control elements and trans-acting protein components. Chromatin unravelling is an essential component of this. The whole process is dynamic and is regulated by external signals mediated by signal transduction cascades and protein kinases. The importance of maintaining correctly controlled transcription is emphasised by the observation that many tumours arise due to the mutation of genes encoding components of the transcription machinery, chromatin regulating complexes or the pathways which modify their activity. We are studying how transcription factors function at the molecular level and how they link to cellular signalling pathways to generate dynamic transcriptional events in the context of a changing chromatin environment.

Specific areas of interest:

  • Mechanisms of signal-mediated gene regulation

  • Transcriptional control modules in oesophageal cancer

  • Signal-mediated transcriptional drivers of stem cell differentiation

                                      

Research interests

 

Molecular mechanisms of gene regulation

Eukaryotic transcriptional control is a complex process involving multiple cis-acting DNA control elements and trans-acting protein components. Chromatin unravelling is an essential component of this. The whole process is dynamic and is regulated by external signals mediated by signal transduction cascades and protein kinases. The importance of maintaining correctly controlled transcription is emphasised by the observation that many tumours arise due to the mutation of genes encoding components of the transcription machinery, chromatin regulating complexes or the pathways which modify their activity. We are studying how transcription factors function at the molecular level and how they link to cellular signalling pathways to generate dynamic transcriptional events in the context of a changing chromatin environment. Current projects:

1. Mechanisms of signal-mediated gene regulation: The receptor tyrosine kinase (RTK) driven pathways are some of the best studied signalling systems, partly due to their frequent deregulation in cancer. However, we know very little about how they impact on gene regulation. We are focussing on the ERK pathway and how this promotes changes in the regulatory chromatin landscape and subsequently on the underlying gene expression programmes. Current projects are focussing on changes to the 3D architecture surrounding growth factor regulated genes and the mechanisms through which promoters are “reset” to respond to activated signalling pathways. This work is closely integrated with our work on studying enhancer function and how they are formed in a temporally choreographed manner during differentiation (see below).

2. Transcriptional control modules in oesophageal cancer: Oesophageal cancer is highly prevalent and yet has poor survival rates, due to a lack of suitable treatments and poor diagnostic and prognostic markers. We are interested in how transcription factors contribute to oesophageal cancer and their relationships to signalling pathways in this context (Mol Cancer, 2015, 14, 69). More recently, we have begun to focus on the regulatory chromatin landscape of oesophageal adenocarcinoma and how this is established and maintained (Plos Genetics, 2017, 13, e1006879). Current projects are focussed on how the regulatory chromatin landscape is re-sculpted through the action of transcription factors during cell fate changes that accompany cancer progression.

3.  Signal-mediated transcriptional drivers of stem cell differentiation: Stem cell differentiation is controlled by the interplay of signalling pathways and transcriptional regulators. These in turn impact on the regulatory chromatin landscape and the underlying transcriptional programmes. Current projects in the lab are designed to understand the control mechanisms involved, including the role of chromatin remodelling complexes and their interplay with transcription factors like FOXK2 (NAR, 2014, 42, 6232). Other projects are studying the formation of enhancers within the changing chromatin environment and how transcription factors direct their formation (Cell Rep, 2014, 7, 1968).

Our approach:  The multitude of transcription factors and signalling pathways in the cell and the complex nature of DNA regulatory elements, means that extensive regulatory networks exist for controlling gene transcription. We are using a balanced approach which melds genome and proteome-wide studies with deep mechanistic investigation to understand how these events are orchestrated. We are using a "systems analysis" approach using a combination of single cell, in silico, and sequencing-based techniques (eg RNAseq, ChIPseq and ATACseq) to probe the networks controlled by transcription factors and coactivators in response to different signalling events (PLoS Genetics, 2012, 8, e1002694). Incorporated into these studies, are mechanistic approaches aimed at understanding how transcription factors orchestrate changes in chromatin structure in response to signalling cues, and particularly how promoters are re-set following temporal activation in response to signalling. These include classical molecular and biochemical techniques, including the latest CRISPR Cas9-based genome editing and manipulation approaches.

 

 

….and a jargon-free summary for the general public…..

Recent technological advances have enabled us to discover the genetic blueprint for life- DNA- in many different organisms. DNA contains all the information required to form a fully functioning organism. However, this information must be accessed and decoded to enable the building blocks of life to be assembled. The basic initial process involved in decoding the genome is called transcription. This is in turn facilitated by chromatin remodelling, which is a process that allows the DNA to become accessible to the transcription machinery. Transcription does not occur constantly and at the same rate throughout the DNA in our genomes, and instead is controlled by molecular switches called transcription factors which themselves are turned on or off in response to signals. The overall aim of the work in my lab is to understand how transcription factors function as molecular switches and respond to signals, and hence are able to control the decoding of specific parts of the genome. Cancer is a disease primarily caused by errors in the genome-decoding process. Furthermore, future disease therapies are being developed based on the utility of stem cells for regenerating damaged tissues. Our work harnesses the latest technologies to focus on transcription factor switches in both these areas.

 

 

Overview

Biography

Andy obtained a first class degree in Biochemistry from Sheffield University, UK, and continued his studies there to complete a PhD studying prokaryotic transcriptional control mechanisms. He subsequently continued his work on prokaryotic transcription factors in his first Postdoc position, and then moved to the Max Planck Institute in Freiburg, Germany to study eukaryotic transcriptional control mechanisms. He secured his first independent group leader position at the University of Newcastle upon tyne in 1992 and moved to the University of Manchester, UK, in 1990 where he secured a Professorship in 2002. He has continued to work on eukarylotic transcriptional control mechansims and how these are controlled by cell signalling pathways. More recently his studies have extended to studying the interplay between chromatin and transcription, and how this changes as cells differentiate or are converted into disease states such as cancer.

Opportunities

Positions available

Generally, applications are welcome at any time for researchers to join the lab. For postdocs, fully funded positions become periodically available but applications from people holding (or likely to obtain) postdoctoral Fellowship are welcome all the time. Help in obtaining funding and designing projects which fit with the interests of the lab is available. Details of the research interests of the lab are highlighted elsewhere on this site.

Short-term placements suitable for undergraduate or early graduate students are also available in the lab. These are particularly targeted at internal masters course students but are also available for students with their own funding (eg Erasmus exchange students). Short summer placements for undergraduates are periodically available.

Applications for PhD positions are also welcome at any time but generally most positions are available for starting in Sept/Oct of any particular year and decisions on acceptance are made around January of the same year. However, for fully funded students, alternative quarterly start dates are possible. A number of project areas and criteria for eligibility/funding are shown below.

My group

 Andy Sharrocks

 Principal Investigator

 

 

 

      Shen-Hsi Yang

      Senior research scientist

      Enhancer activation mechanisms during embronic stem cell differentiation.

 

  Zoulfia Darieva

  Postdoc

  Signal-dependent transcriptional control mechanisms

 

   Samantha Carrera

   Postdoc

   Signal-dependent transcriptional control mechanisms

 

Zongling Ji

Postdoc

Transcription factor- chromatin regulatory complex interplay in human embryonic stem cells

 

Danielle Owen

Postdoc

SUMO-dependent regulators of chromatin and transcription

 

Yaoyong Li

Postdoc

Bioinformatics analysis of gene regulatory mechanisms

 

   Connor Rogerson

   PhD student

   Transcriptional control networks in oesophageal cancer

 

   Rotem Lesham

   PhD student

   SUMO-dependent activities of chromatin regulatory complexes

 

   Sam Ogden

   PhD student

   RTK signalling networks in oesophageal cancer

 

 Will Bleaney

 PhD student

 The regulatory chromatin landscape in oesophageal cancer

 

 

Guanhua Yan

Research technician

 

 

 

Alumni

Nineteen PhD students have trained in the lab and 15 of these went on to further research posts after completing their PhDs. Three of these now run their own research groups. Others have established careers in public engagement, clinical trials coordination and clinical practice. Three MD students have also trained in the lab and all have gone on to further their clinical careers as consultants. In addition, 18 Postdocs have trained in the lab, and four of these have gone on to establish their own research groups.

Expertise related to UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

Research Beacons, Institutes and Platforms

  • Digital Futures

Keywords

  • Gene regulation
  • Chromatin
  • Transcription
  • Signalling
  • SUMO
  • phosphorylation
  • ATAC-seq
  • ChIP-seq
  • RNA-seq
  • Oesophageal cancer
  • Stem cells

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