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In vivo spatiotemporal mapping of genome-wide motions and gene-level transcriptional activity via integrated experimental platform and data-analytical pipeline

Award Number: R01GM145924
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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In vivo spatiotemporal mapping of genome-wide motions and gene-level transcriptional activity via integrated experimental platform and data-analytical pipeline - Summary: The human genome is highly dynamic, yet the principles governing its movement are not known. Locally, chromatin undergoes constant remodeling and rearrangement associated with processes such as transcription, replication and DNA repair. At large length scales, chromatin dynamics is coherent over microns and seconds. How the local gene-level processes contribute to nucleus-wide chromatin motions remains an open question. To address this question, our overall approach is to map spatially and temporally resolved chromatin dynamics across the nucleus in mammalian cells in vivo, while connecting it with motion and transcriptional activity of specific genomic loci in real time. To do so, we will develop crosscutting tools integrating synergistically quantitative approaches derived from the physical sciences with the latest techniques from molecular biology and biochemistry. We will build an integrated experimental and analytical platform enabling simultaneous measurements of nucleus-wide and gene-specific motions in real time in vivo (Aim 1). Specifically, we will establish a data collection and analytical pipeline mapping chromatin motions across the nucleus in vivo using displacement correlation spectroscopy (DCS), while monitoring motions of genes visualized by CRISPR/dCas9 technology and tracked via new machine-learning assisted algorithms. In addition, our platform will monitor the spatiotemporal heterogeneity of chromatin across nucleus and toggle transcriptional activity of the tracked genes. Using this integrated platform, we will address the fundamental question of how gene-level transcription activity contributes to genome-wide motions (Aim 2). We will measure maps of chromatin motions and compaction across the whole genome, while simultaneously determining the local compaction and mobility of specific genes (MUC4, IL6) as a function of their transcriptional activity. Our findings will paint a new picture of the complexity and interconnectedness of gene- and genome-level dynamics and spatial heterogeneity. Finally, we will extend this approach to study interphase chromatin dynamics and compaction before and after cell differentiation of mouse embryonic stem cells (Aim 3). By linking gene-level activity to genome-wide compaction and motions, these results will have important implications for elucidating the role of chromatin dynamics in gene regulation and expression. Moreover, such knowledge will provide a framework for a mechanistic picture of chromatin dynamics in mammalian cells.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $324,316 )
2025	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	4	4/15/2025	NON-COMPETING CONTINUATION	$324,316
														Subtotal = $324,316

Issue Date FY: 2024 ( Subtotal = $324,316 )
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	3	4/10/2024	NON-COMPETING CONTINUATION	$291,885
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	001	3	7/15/2024	NON-COMPETING CONTINUATION	$32,431
														Subtotal = $324,316

Issue Date FY: 2023 ( Subtotal = $324,004 )
2023	2023	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	2	4/4/2023	NON-COMPETING CONTINUATION	$324,004
														Subtotal = $324,004

Issue Date FY: 2022 ( Subtotal = $342,947 )
2022	2022	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	1	7/11/2022	NEW	$342,947
														Subtotal = $342,947

Grand Total All Awards = $1,315,583

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In vivo spatiotemporal mapping of genome-wide motions and gene-level transcriptional activity via integrated experimental platform and data-analytical pipeline

Award Number: R01GM145924

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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