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Yamini Dalal, Ph.D.

Yamini Dalal, Ph.D.

  • Center for Cancer Research
  • National Cancer Institute
Group Director, Chromosome Structure and Epigenetic Mechanisms Group

RESEARCH SUMMARY

Our lab focuses on proteins called histones, which package the entirety of the human genome into a nucleoprotein complex called chromatin. Specific regions of chromatin are prone to fragility and chromosomal rearrangements in cancer cells. Consequently, understanding how this protein complex is mis-regulated is important in understanding chromosome fragility. Using a combination of chromatin biochemistry, computational modeling, single molecule microscopy, genetics, genomics and cell biology, we are currently investigating whether histone complexes can adopt alternate structural conformations in cancer cells, and the functional consequences of such alterations upon the cancer epigenome.

Areas of Expertise

Chromatin/Nucleosome Structure
Epigenetics
Atomic Force and Electron Microscopy

Publications

Selected Key Publications

Centromere inactivation during aging can be rescued in human cells

Sweta Sikder, Songjoon Baek, Truman McNeil, Yamini Dalal
Molecular Cell. 85(4): 692-707, 2025.
Full-Text Article(link is external)
[ Journal Article ]

High-resolution analysis of human centromeric chromatin

Daniël P Melters, Minh Bui, Tatini Rakshit, Sergei A Grigoryev, David Sturgill, Yamini Dalal
Life Science Alliance. 8(4): 2025.
Full-Text Article(link is external)
[ Journal Article ]

Native and tagged CENP-A histones are functionally inequivalent

Minh Bui, Songjoon Baek, Reda S Bentahar, Daniël P Melters, Yamini Dalal
Epigenetics & Chromatin. 17(1): 2024.
Full-Text Article(link is external)
[ Journal Article ]

The role of cryptic ancestral symmetry in histone folding mechanisms across Eukarya and Archaea

Haiqing Zhao, Hao Wu, Alex Guseman, Dulith Abeykoon, Christina M Camara, Yamini Dalal, David Fushman, Garegin A Papoian
PLoS Computational Biology. 20(1): 2024.
Full-Text Article(link is external)
[ Journal Article ]

Single molecule analysis of CENP-A chromatin by high-speed atomic force microscopy

Daniël P Melters, Keir C Neuman, Reda S Bentahar, Tatini Rakshit, Yamini Dalal
eLife. 12: 2023.
Full-Text Article(link is external)
[ Journal Article ]

Biography

Yamini Dalal, Ph.D.
Senior Investigator

Yamini Dalal, Ph.D.

Dr. Yamini Dalal became interested in chromosome structure and epigenetic gene regulation during her Baccalaureate years at St. Xavier's College, Bombay, India, where she graduated with a double major in Biochemistry and Life Sciences in 1995. She moved to the United States for her post-graduate work. In Arnold Stein's laboratory at Purdue University, she used classical chromatin biochemistry tools to understand how DNA sequence motifs and linker histones can shape the chromatin structure in silico, in vitro, and in vivo. During this time, she discovered that the regions of the mouse genome contained alternating tracts of stiff and flexible DNA, which allowed in silico prediction of nucleosome positions. These positions could be recapitulated in vitro using just purified histones and DNA, and detected in vivo, at developmentally regulated genes in mice. She also studied how linker histone H1 could influence nucleosome positioning and chromatin folding in vitro and in vivo. For these studies, she received her Ph.D. from Purdue University in 2003. Histone variants were the next logical step in teasing out how intrinsic variability in the chromatin fiber can encode a diversity of biological functions. To study this aspect of chromatin structure, Yamini moved to Seattle to work with Dr. Steven Henikoff at the Fred Hutchinson Cancer Research Center from 2003-2007. Her lab focuses on proteins called histones and their variants, which package the entirety of the human genome into a nucleoprotein complex called chromatin in vivo. Specific regions of chromatin are prone to fragility and chromosomal rearrangements in cancer cells. Using a combinatorial interdisciplinary toolset in colorectal and brain cancer cells and tissues, they investigate the structural and functional consequences of epigenetic alterations within the cancer epigenome, and the therapeutic potential of small molecule suppressors to target these aberrant pathways. She was awarded tenure at NIH in 2018. In 2021, Dr. Dalal became Senior Advisor for Faculty Development, CCR Office of Scientific Programs.

Job Vacancies

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Covers

High-resolution analysis of human centromeric chromatin

High-resolution analysis of human centromeric chromatin

Published Date

About the Cover: 

The essential kinetochore component CENP-C is critical in regulating centromere homeostasis. The image shows a multipolar spindle metaphase cell, a consequence when CENP-C is overexpressed. Mitotic spindles (cyan) attach to the chromosomes (grey) via the kinetochore (CENP-C in red).

Abstract:

Centromeres are marked by the centromere-specific histone H3 variant CENP-A/CENH3. Throughout the cell cycle, the constitutive centromere-associated network is bound to CENP-A chromatin, but how this protein network modifies CENP-A nucleosome conformations in vivo is unknown. Here, we purify endogenous centromeric chromatin associated with the CENP-C complex across the cell cycle and analyze the structures by single-molecule imaging and biochemical assays. CENP-C complex–bound chromatin was refractory to MNase digestion. The CENP-C complex increased in height throughout the cell cycle culminating in mitosis, and the smaller CENP-C complex corresponds to the dimensions of in vitro reconstituted constitutive centromere-associated network. In addition, we found two distinct CENP-A nucleosomal configurations; the taller variant was associated with the CENP-C complex. Finally, CENP-A mutants partially corrected CENP-C overexpression–induced centromeric transcription and mitotic defects. In all, our data support a working model in which CENP-C is critical in regulating centromere homeostasis by supporting a unique higher order structure of centromeric chromatin and altering the accessibility of the centromeric chromatin fiber for transcriptional machinery.

Citation
Daniël P Melters, Minh Bui, Tatini Rakshit, Sergei A Grigoryev, David Sturgill, Yamini Dalal
Life Science Alliance Jan 2025, 8 (4) e202402819; DOI: 10.26508/lsa.202402819
A "construction worker" lncRNA hammering a CENP-A "nail" into a chromosome, causing a break.

Oncogenic lncRNAs alter epigenetic memory at a fragile chromosomal site in human cancer cells

Published Date

About the Featured Article

In cancer cells, histone H3 variant CENP-A is innately overexpressed and mislocalized to regions outside centromeres, typically to chromosome arms and telomeres. Transcription and transcripts of specific oncogenic lncRNAs could serve as a recruitment signal for CENP-A mislocalization. Thus, the oncogenic lncRNA-based mechanism of CENP-A mislocalization can generate aberrant epigenetic signatures resulting in chromosome breaks and amplification in the cancer epigenome.

https://www.science.org/doi/10.1126/sciadv.abl5621(link is external)

Abstract

Chromosome instability is a critical event in cancer progression. Histone H3 variant CENP-A plays a fundamental role in defining centromere identity, structure, and function but is innately overexpressed in several types of solid cancers. In the cancer background, excess CENP-A is deposited ectopically on chromosome arms, including 8q24/cMYC locus, by invading transcription-coupled H3.3 chaperone pathways. Up-regulation of lncRNAs in many cancers correlates with poor prognosis and recurrence in patients. We report that transcription of 8q24-derived oncogenic lncRNAs plays an unanticipated role in altering the 8q24 chromatin landscape by H3.3 chaperone–mediated deposition of CENP-A–associated complexes. Furthermore, a transgene cassette carrying specific 8q24-derived lncRNA integrated into a naïve chromosome locus recruits CENP-A to the new location in a cis-acting manner. These data provide a plausible mechanistic link between locus-specific oncogenic lncRNAs, aberrant local chromatin structure, and the generation of new epigenetic memory at a fragile site in human cancer cells.

Citation

SCIENCE ADVANCES, 2 Mar 2022, Vol 8, Issue 9. DOI: 10.1126/sciadv.abl5621

Schematic representation of H1 binding modes.

A Glitch in the Snitch: the role of linker histone H1 in shaping the epigenome in normal and diseased cells

Published Date

About the cover

Schematic representation of H1 binding modes. Image credit: Ankita Saha and Yamini Dalal.

Taken from Open Biology article “A Glitch in the Snitch: the role of linker histone H1 in shaping the epigenome in normal and diseased cells” DOI: 10.1098/rsob.210124(link is external)

Abstract

Histone H1s or the linker histones are a family of dynamic chromatin compacting proteins that are essential for higher-order chromatin organization. These highly positively charged proteins were previously thought to function solely as repressors of transcription. However, over the last decade, there is a growing interest in understanding this multi-protein family, finding that not all variants act as repressors. Indeed, the H1 family members appear to have distinct affinities for chromatin and may potentially affect distinct functions. This would suggest a more nuanced contribution of H1 to chromatin organization. The advent of new technologies to probe H1 dynamics in vivo, combined with powerful computational biology, and in vitro imaging tools have greatly enhanced our knowledge of the mechanisms by which H1 interacts with chromatin. This family of proteins can be metaphorically compared to the Golden Snitch from the Harry Potter series, buzzing on and off several regions of the chromatin, in combat with competing transcription factors and chromatin remodellers, thereby critical to the epigenetic endgame on short and long temporal scales in the life of the nucleus. Here, we summarize recent efforts spanning structural, computational, genomic and genetic experiments which examine the linker histone as an unseen architect of chromatin fibre in normal and diseased cells and explore unanswered fundamental questions in the field.

Citation

Saha Ankita(link is external) and Dalal Yamini(link is external) 2021 A glitch in the snitch: the role of linker histone H1 in shaping the epigenome in normal and diseased cells Open Biol. 11210124210124  http://doi.org/10.1098/rsob.210124(link is external)

Journal of Molecular Biology Cover - March 19, 2021; Vol. 433, Issue 6

Diving into Chromatin Across Time and Space

Published Date

About the Cover:

This special issue “Diving into chromatin structure across space and time” highlights the application of cutting-edge approaches to further illuminate transactions that occur on, and by, the chromatin fiber. Appropriately for this year of covid, where virtual life is a simulacrum of reality, we start at one end of the scale - computational modeling of dynamic nucleoprotein complexes.

Citation

Dalal Y, Panchenko AR. Diving into Chromatin across Space and Time. J Mol Biol. 2021 Mar 19;433(6):166884. doi: 10.1016/j.jmb.2021.166884. Epub 2021 Feb 20. PMID: 33621519.

Promiscuous histone mis-assembly is actively prevented by chaperones

Promiscuous histone mis-assembly is actively prevented by chaperones

Published Date

About the Cover

Chaperone HJURP drives the proper loading of protein CENP-A to the centromere of a chromosome. The effect of HJURP on CENP-A's structural dynamics are observed and explained using dual-resolution in silico simulations, while in vivo experiments demonstrate how CENP-A mutations influence its specific localization in human cells.

Abstract

Histone proteins are essential for the organization, expression, and inheritance of genetic material for eukaryotic cells. A centromere-specific H3 histone variant, centromere protein A (CENP-A), shares about 50% amino acid sequence identity with H3. CENP-A is required for packaging the centromere and for the proper separation of chromosomes during mitosis. Despite their distinct biological functions, previously reported crystal structures of the CENP-A/H4 and H3/H4 dimers reveal a high degree of similarity. In this work, we characterize the structural dynamics of CENP-A/H4 and H3/H4 dimers based on a dual-resolution approach, using both microsecond-scale explicit-solvent all-atom and coarse-grained (CG) molecular dynamics (MD) simulations. Our data show that the H4 histone is significantly more rigid compared with the H3 histone and its variant CENP-A, hence, serving as a reinforcing structural element within the histone core. We report that the CENP-A/H4 dimer is significantly more dynamic than its canonical counterpart H3/H4, and our results provide a physical explanation for this flexibility. Further, we observe that the centromere-specific chaperone Holliday Junction Recognition Protein (HJURP) stabilizes the CENP-A/H4 dimer by forming a specific electrostatic interaction network. Finally, replacing CENP-A S68 with E68 disrupts the binding interface between CENP-A and HJURP in all-atom MD simulation, and consistently, in vivo experiments demonstrate that replacing CENP-A S68 with E68 disrupts CENP-A’s localization to the centromere. Based on all our results, we propose that, during the CENP-A/H4 deposition process, the chaperone HJURP protects various substructures of the dimer, serving both as a folding and binding chaperone.

Citation

Promiscuous histone mis-assembly is actively prevented by chaperones(link is external). Zhao, Haiqing+; Winogradoff, David+; Bui, Minh; Dalal, Yamini*; and Papoian, Garegin*.  J Am Chem Soc. 138(40):  13083-13446,  2016. +equal contribution; *corresponding authors.  Note:  Haiqing Zhao is a joint graduate student who was funded for 2 years by the NCI-University of Maryland Partnership for Integrative Cancer Research.

Alumni

Arun Kumar Ganesan, Ph.D., Assistant Professor, University of New Mexico
Arun Kumar Ganesan, Ph.D., Assistant Professor, University of New Mexico
2018-2023
Postdoctoral Fellow (Visiting)
Chieh-Ren (Jeremiah) Hsia, Ph.D.
Chieh-Ren (Jeremiah) Hsia, Ph.D.
2021-2024
Postdoctoral Fellow (Visiting)
Reda Bentahar, B.S., Manufacturing Associate, Macrogenics
Reda Bentahar, B.S., Manufacturing Associate, Macrogenics
2022-2023
Postbaccalaureate Fellow
Ankita Saha, Ph.D., Albert Einstein College of Medicine
Ankita Saha, Ph.D., Albert Einstein College of Medicine
2019-2022
Postdoctoral Fellow (Visiting)
Ali Aljasser, M.S., Graduate Research Assistant, Catholic University of America
Ali Aljasser, M.S., Graduate Research Assistant, Catholic University of America
2020
Predoctoral Fellow
Mary Pitman, Ph.D., Postdoctoral Fellow, UC Irvine
Mary Pitman, Ph.D., Postdoctoral Fellow, UC Irvine
2015-2019
Predoctoral Fellow
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