Sankari Nagarajan

Dr

  • C.2260 Michael Smith Building, Oxford Road, The University of Manchester

    M13 9PT Manchester

    United Kingdom

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Personal profile

Research interests

Nagarajan lab is interested in unravelling the mechanisms of enhancer regulation and the role of transcription factors in mediating the progression to drug resistance and metastasis in aggressive cancers. We utilise single cell analyses, functional genomic technologies, quantitative chromatin-based proteomics and CRISPR-Cas9 assays to decipher the mechanisms of transcription. We work on the following projects:

1. Understanding the role of chromatin-associated proteins in driving endocrine resistance in breast and prostate cancers

We established CRISPR-Cas9 based genome-wide knockout screens to identify the proteins involved in promoting or deregulating endocrine resistance in breast cancers upon Tamoxifen and Fulvestrant treatment and in prostate cancers upon Enzalutamide treatment. This screen identified multiple chromatin architecture proteins involved in controlling the resistance of cell growth during drug treatments. Some of these proteins are amplified/mutated in breast and prostate cancers, especially prevalent in secondary tumours. Given the importance of these proteins clinically and evident from molecular analyses, we aim to identify the mechanisms behind the regulation of endocrine resistance by these chromatin-associated proteins and how these proteins interact with nuclear receptors (estrogen and androgen receptor) to bring cell growth resistance towards treatments. We will employ cutting-edge technologies studying gene regulation and chromatin organization-based assays to understand how enhancer -promoter interactions and their deregulation are involved in these processes.

2. Deciphering the activity of enhancers and transcription factors regulated by chromatin remodelling complexes

Nagrajan et al., 2020 identied the importance of chromatin remodelling complex, SWI/SNF in ER+ breast cancers in driving tumour suppressor activity and controlling response to ER-targeting drugs. In ER+ breast cancers, mutations in SWI/SNF subunits are enriched in relapsed/metastatic cancers. Even though, these mutations are well-studied in other cancers, their regulation in breast cancers is largely unknown. Our lab intends to identify the role of SWI/SNF-A (BAF) and SWI/SNF-B (P-BAF) in breast cancers and how their inactivation leads to uncontrolled growth and metastasis. We propose that SWI/SNF complex mediates these processes, not only by affecting chromatin accessibility, but also by associating with transcription factors and nuclear receptors.

3. Single cell epigenomics to investigate the molecular mechanisms of metastasis in aggressive cancers

The advances in single cell epigenomics have grown upto an extent that we can investigate both transcription and chromatin accessibility in the same cell simultaneously. Using the recent progress in 10X genomics, we intend to study the epigenetic regulation and processed involved in metastasis in breast cancers.

4. Enhancer-derived RNAs as markers for enhancer regulation in aggressive breast cancers

Recent evidences substantially support the importance of noncoding RNAs derived from enhancers (shortly eRNAs) in promoting corresponding gene expression. Our lab pioneered in identifying the unstable and low copy number enhancer RNAs using RNA-FISH based assays. We aim to expand this technology and other genome-wide nascent RNA analyses to identify the eRNAs deregulated during specific processes involved in aggressiveness in breast cancers.

Prizes and awards

 

  • CRUK Career Establishment Award (2021-2027), Project title: Understanding the role of Mediator and Cohesin complexes during endocrine resistance in breast and prostate cancers
  • UKIBCS Poster Prize, UK Interdisciplinary Breast Cancer Symposium, Birmingham, 2020
  • EMBO Poster Prize, EMBO Workshop Nuclear Receptors and Biological Networks, 2018
  • GRC Poster prize, Hormone-dependent cancers, Gordon Research Conference, 2017
  • GZMB PhD award, Best PhD award, GZMB Universität Göttingen, Germany, 2015

Memberships of committees and professional bodies

  • Principal Investigator in Manchester Breast Centre (MBC)
  • Principal Investigator in Manchester Cancer Research Centre (MCRC)
  • Member in EACR, BACR and AACR
  • EACR Ambassador
  • Selection panel member for PhD studentship in Manchester Cancer Research Centre (MCRC)

Biography

I am a breast cancer research scientist with around 10 years of research experience investigating the transcriptional regulation of disease progression in breast cancers. I completed my Integrated M.Sc. in Bio-Medical Science at Bharathidasan University, Trichy, India. After obtainining a prestigious and competitive PhD scholarship from German Academic Exchange Service (DAAD), I moved to the University of Goettingen, Germany, to work with Prof. Dr. Steven A Johnsen, for my PhD. My successful PhD research on an epigenetic reader protein BRD4 in ER+ breast cancers introduced the possibility of using Bromodomain and Extraterminal domain-containing protein (BET) inhibitors as a therapeutic strategy against breast cancers. This body of work resulted in me being awarded best PhD from my graduate program, Göttingen Graduate Center for Neurosciences, Biophysics, and Molecular Biosciences.

As a Research associate, I worked with Prof. Jason Carroll, CRUK Cambridge Instiutute. Using genome-wide CRISPR-based drug resistance screens and functional genomic approaches (ChIP-seq, ATAC-seq, RNA-seq), I investigated a novel role for the SWI/SNF chromatin remodelling complex, and its subunit ARID1A in controlling endocrine treatment response. As a result of my achievements, I got promoted as a Senior Research Associate at CRUK Cambridge Institute. Then, I moved to Manchester to start my first PI position in the Division of Molecular and Cellular Function. Based on my research findings from CRISPR screening, I developed an independent grant proposal as a PI on chromatin architecture proteins in ER+  breast cancers and this was recently awarded a Career Establishment award by the charity Cancer Research UK. My research lab at Manchester will extend my experience on chromatin remodelling and breast cancer epigenetics using CRISPR-Cas9 system and single cell epigenomic approaches into a new direction of research: understanding the enhancer evolution during endocrine resistance and metastatic processes in aggressive cancers.

 

 

Job vacancies

No positions available at the moment. 

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

Education/Academic qualification

Doctor of Philosophy, Role of BRD4 and histone acetylation in estrogen receptor positive breast cancers, Georg-August-Universitat Gottingen

1 Oct 201118 May 2015

Award Date: 11 Sept 2015

Master in Science, Bio-Medical Science, Bharathidasan University

10 Jul 200531 Mar 2010

Award Date: 30 Apr 2010

External positions

Senior Research Associate, Cancer Research UK Cambridge Institute

11 Dec 201930 Jun 2020

Research Associate, Cancer Research UK Cambridge Institute

2 Nov 201511 Dec 2019

Postdoctoral fellow, Georg-August-Universitat Gottingen

1 Apr 201531 Oct 2015

Areas of expertise

  • Q Science (General)
  • Epigenetics
  • Enhancer regulation
  • Chromatin remodelling
  • Breast cancer
  • Metastasis
  • CRISPR
  • Drug resistance
  • Enhancer RNAs

Research Beacons, Institutes and Platforms

  • Cancer

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