Diana Hargreaves

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Diana Hargreaves
Diana Hargreaves.jpg
Alma mater Haverford College,
Yale University
Known forstudies on BAF complex
Scientific career
Institutions Salk Institute for Biological Sciences
Website https://www.salk.edu/scientist/diana-hargreaves/

Diana Hargreaves is an American biologist and assistant professor at The Salk Institute for Biological Studies and member of The Salk Cancer Center. Her laboratory focuses on epigenetic regulation by the BAF (SWI/SNF) chromatin remodeling complexes in diverse physiological processes including development, immunity, and diseases such as cancer. [1]

Contents

Early life and education

Hargreaves completed her Bachelor of Science in Chemistry at Haverford College, a leading liberal arts college in Haverford Pennsylvania. Hargreaves obtained her PhD in Immunology at Yale University where she studied in the lab of Ruslan Medzhitov, a leader in the field of innate immunity and pathogen recognition. [2] Her thesis focused on the epigenetic signatures following pathogen recognition by innate immune cells such as macrophages. [3]

Career and research

Following the completion of her Doctoral work, Hargreaves joined the lab of Dr. Gerald Crabtree where she and others uncovered that the genes encoding subunits of the BAF Chromatin remodelling subunits are mutated in ~20% of all human cancers and uncovered mechanisms of BAF complex tumor suppression. [4] Hargreaves was appointed professorship at the Salk Institute for Biological Studies in 2015 where she continues her focus on the chromatin remodelling complex BAF. [5] Her lab has recently discovered a specific subunit of BAF that is responsible for maintaining cellular pluripotency, an unbiased differentiation state. [6] Hargreaves' work holds potential in the realm of regenerative medicine for use in treating tissue damage and disease. [7] Hargreaves also investigates epigenetic chromatin remodelling with a goal of identifying therapeutic targets that harness the immune system to defend against tumors. [8]

Rewards and honors

Publications

Related Research Articles

RSC is a member of the ATP-dependent chromatin remodeler family. The activity of the RSC complex allows for chromatin to be remodeled by altering the structure of the nucleosome.

<span class="mw-page-title-main">SWI/SNF</span> Subfamily of ATP-dependent chromatin remodeling complexes

In molecular biology, SWI/SNF, is a subfamily of ATP-dependent chromatin remodeling complexes, which is found in eukaryotes. In other words, it is a group of proteins that associate to remodel the way DNA is packaged. This complex is composed of several proteins – products of the SWI and SNF genes, as well as other polypeptides. It possesses a DNA-stimulated ATPase activity that can destabilize histone-DNA interactions in reconstituted nucleosomes in an ATP-dependent manner, though the exact nature of this structural change is unknown. The SWI/SNF subfamily provides crucial nucleosome rearrangement, which is seen as ejection and/or sliding. The movement of nucleosomes provides easier access to the chromatin, allowing genes to be activated or repressed.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">SMARCA4</span> Protein-coding gene in the species Homo sapiens

Transcription activator BRG1 also known as ATP-dependent chromatin remodeler SMARCA4 is a protein that in humans is encoded by the SMARCA4 gene.

<span class="mw-page-title-main">SMARCB1</span> Protein-coding gene in the species Homo sapiens

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 is a protein that in humans is encoded by the SMARCB1 gene.

<span class="mw-page-title-main">SMARCA2</span> Protein-coding gene in the species Homo sapiens

Probable global transcription activator SNF2L2 is a protein that in humans is encoded by the SMARCA2 gene.

<span class="mw-page-title-main">ACTL6A</span> Protein-coding gene in the species Homo sapiens

Actin-like protein 6A is a protein that in humans is encoded by the ACTL6A gene.

<span class="mw-page-title-main">ARID1A</span> Protein-coding gene in humans

AT-rich interactive domain-containing protein 1A is a protein that in humans is encoded by the ARID1A gene.

<span class="mw-page-title-main">SMARCC1</span> Protein-coding gene in the species Homo sapiens

SWI/SNF complex subunit SMARCC1 is a protein that in humans is encoded by the SMARCC1 gene.

<span class="mw-page-title-main">SMARCE1</span> Protein-coding gene in the species Homo sapiens

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1 is a protein that in humans is encoded by the SMARCE1 gene.

<span class="mw-page-title-main">SMARCC2</span> Protein-coding gene in the species Homo sapiens

SWI/SNF complex subunit SMARCC2 is a protein that in humans is encoded by the SMARCC2 gene.

<span class="mw-page-title-main">ARID1B</span> Protein-coding gene in humans

AT-rich interactive domain-containing protein 1B is a protein that in humans is encoded by the ARID1B gene. ARID1B is a component of the human SWI/SNF chromatin remodeling complex.

<span class="mw-page-title-main">SMARCD1</span> Protein-coding gene in the species Homo sapiens

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 is a protein that in humans is encoded by the SMARCD1 gene.

<span class="mw-page-title-main">PBRM1</span> Protein-coding gene in the species Homo sapiens

Protein polybromo-1 (PB1) also known as BRG1-associated factor 180 (BAF180) is a protein that in humans is encoded by the PBRM1 gene.

<span class="mw-page-title-main">SMARCD3</span> Protein-coding gene in the species Homo sapiens

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 3 is a protein that in humans is encoded by the SMARCD3 gene.

<span class="mw-page-title-main">SMARCD2</span> Protein-coding gene in the species Homo sapiens

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 is a protein that in humans is encoded by the SMARCD2 gene.

Gerald R. Crabtree is the David Korn Professor at Stanford University and an Investigator in the Howard Hughes Medical Institute. He is known for defining the Ca2+-calcineurin-NFAT signaling pathway, pioneering the development of synthetic ligands for regulation of biologic processes and discovering chromatin regulatory mechanisms involved in cancer and brain development. He is a founder of Ariad Pharmaceuticals, Amplyx Pharmaceuticals, and Foghorn Therapeutics.

<span class="mw-page-title-main">Transcriptional memory</span>

Transcriptional memory is a biological phenomenon, initially discovered in yeast, during which cells primed with a particular cue show increased rates of gene expression after re-stimulation at a later time. This event was shown to take place: in yeast during growth in galactose and inositol starvation; plants during environmental stress; in mammalian cells during LPS and interferon induction. Prior work has shown that certain characteristics of chromatin may contribute to the poised transcriptional state allowing faster re-induction. These include: activity of specific transcription factors, retention of RNA polymerase II at the promoters of poised genes, activity of chromatin remodeling complexes, propagation of H3K4me2 and H3K36me3 histone modifications, occupancy of the H3.3 histone variant, as well as binding of nuclear pore components. Moreover, locally bound cohesin was shown to inhibit establishment of transcriptional memory in human cells during interferon gamma stimulation.

Robert E. Kingston is an American biochemist who studies the functional and regulatory role nucleosomes play in gene expression, specifically during early development. After receiving his PhD (1981) and completing post-doctoral research, Kingston became an assistant professor at Massachusetts General Hospital (1985), where he started a research laboratory focused on understanding chromatin's structure with regards to transcriptional regulation. As a Harvard graduate himself, Kingston has served his alma mater through his leadership.

Cigall Kadoch is an American biochemist and cancer biologist who is Associate Professor of Pediatric Oncology at the Dana–Farber Cancer Institute and Harvard Medical School and an Investigator at the Howard Hughes Medical Institute. Her research is focused in chromatin regulation and how changes in cellular structure can lead to human diseases, such as Cancer, Neurodevelopmental disorders, and others. She is internationally recognized for her work on the mammalian SWI/SNF complex, a large molecular machine known as a Chromatin remodeling complex. She was named as one of the world's leading scientists by MIT Technology Review, 35 Under 35 and Forbes 30 Under 30, and a Finalist for the Blavatnik Awards for Young Scientists. In 2019, she received the Martin and Rose Wachtel Cancer Research Prize from the American Association for the Advancement of Science and in 2020, the American Association for Cancer Research Outstanding Achievement in Basic Cancer Research Award. Kadoch was also recognized as one of the 100 Influential Women in Oncology by OncoDaily.

References

  1. ↑ "Diana Hargreaves". Salk Institute for Biological Studies. Retrieved 2019-09-07.
  2. ↑ "Diana Hargreaves". Salk Institute for Biological Studies. Retrieved 2019-09-07.
  3. ↑ Medzhitov, Ruslan; Hargreaves, Diana C.; Foster, Simmie L. (June 2007). "Gene-specific control of inflammation by TLR-induced chromatin modifications". Nature. 447 (7147): 972–978. Bibcode:2007Natur.447..972F. doi:10.1038/nature05836. ISSN   1476-4687. PMID   17538624. S2CID   4426398.
  4. ↑ Crabtree, Gerald R.; Zhao, Keji; Cho, Yoon-Jae; Pfister, Stefan; Marcel Kool; Korshunov, Andrey; Cui, Kairong; Miller, Erik L.; Hargreaves, Diana C. (May 2013). "BAF complexes facilitate decatenation of DNA by topoisomerase IIα". Nature. 497 (7451): 624–627. Bibcode:2013Natur.497..624D. doi:10.1038/nature12146. ISSN   1476-4687. PMC   3668793 . PMID   23698369.
  5. ↑ "Diana Hargreaves". Salk Institute for Biological Studies. Retrieved 2019-09-11.
  6. ↑ "Maintaining the unlimited potential of stem cells". Salk Institute for Biological Studies. Retrieved 2019-09-11.
  7. ↑ "Maintaining the unlimited potential of stem cells". Salk Institute for Biological Studies. Retrieved 2019-09-11.
  8. ↑ "Salk scientist Diana Hargreaves named Pew-Stewart Scholar for innovative cancer research". Salk Institute for Biological Studies. Retrieved 2019-09-11.
  9. ↑ "Diana Hargreaves". Salk Institute for Biological Studies. Retrieved 2019-09-07.
  10. ↑ Foster, Simmie L.; Hargreaves, Diana C.; Medzhitov, Ruslan (June 2007). "Gene-specific control of inflammation by TLR-induced chromatin modifications". Nature. 447 (7147): 972–978. Bibcode:2007Natur.447..972F. doi:10.1038/nature05836. ISSN   0028-0836. PMID   17538624. S2CID   4426398.
  11. ↑ Hargreaves, Diana C.; Horng, Tiffany; Medzhitov, Ruslan (July 2009). "Control of Inducible Gene Expression by Signal-Dependent Transcriptional Elongation". Cell. 138 (1): 129–145. doi:10.1016/j.cell.2009.05.047. PMC   2828818 . PMID   19596240.
  12. ↑ Kadoch, Cigall; Hargreaves, Diana C; Hodges, Courtney; Elias, Laura; Ho, Lena; Ranish, Jeff; Crabtree, Gerald R (June 2013). "Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy". Nature Genetics. 45 (6): 592–601. doi:10.1038/ng.2628. ISSN   1061-4036. PMC   3667980 . PMID   23644491.
  13. ↑ Kelso, Timothy W R; Porter, Devin K; Amaral, Maria Luisa; Shokhirev, Maxim N; Benner, Christopher; Hargreaves, Diana C (2017-10-02). "Chromatin accessibility underlies synthetic lethality of SWI/SNF subunits in ARID1A-mutant cancers". eLife. 6: e30506. doi: 10.7554/eLife.30506 . ISSN   2050-084X. PMC   5643100 . PMID   28967863.
  14. ↑ Gatchalian, Jovylyn; Malik, Shivani; Ho, Josephine; Lee, Dong-Sung; Kelso, Timothy W. R.; Shokhirev, Maxim N.; Dixon, Jesse R.; Hargreaves, Diana C. (December 2018). "A non-canonical BRD9-containing BAF chromatin remodeling complex regulates naive pluripotency in mouse embryonic stem cells". Nature Communications. 9 (1): 5139. Bibcode:2018NatCo...9.5139G. doi:10.1038/s41467-018-07528-9. ISSN   2041-1723. PMC   6277444 . PMID   30510198.
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