Email

graham.erwin@bcm.edu

Positions

Assistant Professor

Molecular & Human Genetics
Baylor College of Medicine

Faculty Member

Dan L. Duncan Comprehensive Cancer Center (DLDCCC)

Addresses

Lab Address (Lab)

1 Baylor Plz
Houston, TX 77030
United States

Education

PhD from University of Wisconsin–Madison

09/2016 - Madison, Wisconsin United States

Biochemistry

Postdoctoral Fellowship at Stanford University

12/2023 - Stanford, California United States

Genetics

Professional Statement

The Erwin Lab studies the functional role of repetitive DNA, the final frontier of the human genome.

Studying repetitive DNA sequences has historically been hindered by a lack of experimental and computational tools. Many genomic studies perform whole genome sequencing, but filter out half of the data with RepeatMasker, a popular tool that identifies repetitive DNA sequences for removal. Currently, over 56% of the human genome is removed from analysis with RepeatMasker.

The result is that outside of neurological conditions, the function of repeat expansions is currently unknown.

We recently reported a class of recurrent repeat expansions in cancer genomes. Many of these repeat expansions were located in or near regulatory regions of the genome, non-coding elements that are central to the expression and mis-expression of genes in normal and disease cells. This finding provides a clear path to test whether they have a functional role through regulating gene expression. This finding is consistent with the observation that many repeat expansions are non-coding and exert their effect through the regulation of gene expression.

Gene expression is highly regulated, and defects in this process lead to a host of diseases. We showed that programmable DNA-binding polyamides target repetitive DNA sequences with high affinity and specificity (Erwin et al, Angewandte Chemie 2014, Erwin et al, PNAS 2016). Based on these findings, we designed and synthesized a new class of sequence-specific, synthetic transcription elongation factors (Syn-TEFs). These molecules are composed of programmable DNA-binding polyamides flexibly tethered to a small molecule (JQ1) that engages the transcription elongation machinery.

This work culminated in Syn-TEF1, a molecule that actively enables transcription across repressive GAA repeats that silence frataxin expression in Friedreich’s ataxia, a terminal neurodegenerative disease with no effective therapy (Erwin et al, Science 2017). Syn- TEF1 defines a modular framework for developing a class of molecules that promote transcription at targeted genomic loci. An analog of Syn-TEF1 is now in Phase 1 clinical trials for patients with Friedreich’s ataxia.

Websites

Selected Publications

• Graham S Erwin, Gamze Gürsoy, Rashid Al-Abri, Ashwini Suriyaprakash, Egor Dolzhenko, Kevin Zhu, Christian R Hoerner, ..., Ryan K C Yuen, Alice C Fan, John T Leppert, Michael A Eberle, Mark Gerstein, Michael P Snyder "Recurrent repeat expansions in human cancer genomes." Nature. 2023 Jan;613:96-102. Pubmed PMID: 36517591
• Graham S Erwin, Matthew P Grieshop, Asfa Ali, Jun Qi, Matthew Lawlor, Deepak Kumar, Istaq Ahmad, Anna McNally, Natalia Teider, ..., Paul M C Park 2, Hasan Mukhtar 6, Achal K Srivastava 3, Mohammed Faruq 4, James E Bradner 2 5, Aseem Z Ansari "Synthetic transcription elongation factors license transcription across repressive chromatin." Science. 2017 Dec;358:1617-1622. Pubmed PMID: 29192133
• Graham S. Erwin, Matthew P. Grieshop, Devesh Bhimsaria, ..., Aseem Z. Ansari "Synthetic genome readers target clustered binding sites across diverse chromatin states." Proc Natl Acad Sci U S A. 2016 Nov;113:E7418-E7427. Pubmed PMID: 27830652

Funding

Development and application of new tools to identify repeat expansions in human diseases - #NIH/NHGRI 4R00HG011467

(01/01/2021 - 12/31/2026) Grant funding from National Institutes of Health

Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), causes more than 30 rare but devastating diseases. Despite their importance to monogenic disease, the frequency and function of repeat expansions are unknown in complex human diseases. A failure to catalog and understand these repeat expansions in human disease will make it impossible to capitalize on this information to develop new TR- targeting therapeutics, which I previously showed can rescue expression of genes dysregulated in disease (Erwin et al., Science 2017). My central hypothesis is that repeat expansions are recurrent in complex human diseases and alter cell function through the regulation of gene expression. While I have extensive training and experience in the study of TRs with chemical biology, molecular biology, and functional genomics, I am new to bioinformatics and human genetics. Therefore, my overall objective is to obtain additional training in bioinformatics and human genetics and to catalog recurrent repeat expansions and determine their relevance to human disease. This study is the next logical step toward my goal of becoming an independent investigator studying TR sequences in the genome. To achieve my goal, I will take full advantage of the excellent training environment at Stanford University. The expected outcomes include a new set of bioinformatic tools to identify repeat expansions (Aim 1) and a catalog of recurrent repeat expansions in human disease (Aim 2), which will provide a new angle to analyze thousands of NIH-funded, publicly-available human genome datasets. Furthermore, characterizing the function of previously-unrecognized, recurrent repeat expansions will determine whether some of these expansions are functionally important for human disease (Aim 3). The proposed study will enable me to apply my background in TR biology to an important problem while receiving additional training in bioinformatics and human genetics and preparing me for a successful career as an independent investigator. These results will illuminate our understanding of the human genome and set the stage for a new class of precision-targeted therapeutics.

Detection and characterization of repeat variants in cancer

(01/01/2024 - 12/31/2028) Grant funding from Cancer Prevention and Research Institute of Texas

Mutations in the genome of cancer cells enable them to undergo cellular transformation. Therefore, understanding the extent and mechanisms of these mutations is crucial for developing targeted therapies and improving patient outcomes. One of the biggest missing pieces in our understanding of the cancer genome lies in repetitive elements of DNA. We believe that a better understanding of variation in repetitive DNA sequences will enhance our understanding of cancer and enable new diagnostics and therapeutics to enhance precision medicine approaches for cancer therapy. To this end, we will catalog repeat variation in cancer and identify the molecular changes that lead to variations in repetitive DNA.