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Exploring the contribution of large tandem repeat DNA to the organization and maintenance of the inactive X chromosome

Award Number: R01GM117003
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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It is well established that at interphase the inactive X chromosome (Xi) adopts a specific 3-dimensional conformation that differs from that of the active X chromosome (Xa). Yet we know very little about how this arrangement is achieved, nor how critical this organization is to maintaining the epigenomic changes that are characteristic of Xi. Human Xi is arranged into at least two distinct types of facultative heterochromatin that occupy approximately a dozen alternating multi-megabase (Mb) domains along the length of the chromosome, that by immunofluorescence gives a striped appearance to the chromosome at metaphase. At interphase heterochromatin of the same type coalesce resulting in Xi arranging itself into two compartments resulting in a bi-partite appearance. Several large (40-400 kilobase) tandem repeat (TR) DNA reside at the boundary between some of these heterochromatin bands on the X chromosome. These TRs adopt an Xi-specific euchromatin organization that is bound by the architectural protein CCCTC-binding factor (CTCF). Despite residing 15-60 Mb apart, the TRs make frequent Xi-specific intra-chromosomal contact. Given this behavior, the TR elements may function as epigenetically regulated Xi-specific chromosome folding elements. Using cutting edge genome engineering tools, the largest of these TRs (DXZ4), has been removed from Xi as the most direct way to test this hypothesis. On the Xa and male X chromosome, DXZ4 is packaged into constitutive heterochromatin, an arrangement that is common to other autosomal TR elements. However, in some male carcinoma cells, DXZ4 has been found to “flip” its chromatin state to one that resembles that seen on Xi. Furthermore, a similar phenomena has been described for several autosomal TR elements in transformed cells as well as at one autosomal TR that is responsible for a form of muscular dystrophy when in this configuration. The ability of large TR DNA to transition between two distinct configurations, and the fact that one form can mediate new long-range chromatin contacts makes understanding how chromatin states are epigenetically regulated at these sequences important. Experiments described in this proposal seek to address, (1) how chromatin states at the TRs are regulated, with an emphasis on the potential role of associated long noncoding RNAs (lncRNAs) that alter in expression as chromatin states change, (2) assess the impact of DXZ4 loss on the maintenance and organization of Xi, and (3) determine if the introduction of TR elements at different locations on the X is sufficient to establish new long-range contacts. It is anticipated that these studies will assess the function of TR DNA on the X chromosome, as well as provide mechanistic insight into the organization and maintenance of Xi territory and the role of lncRNAs in regulating chromatin at large TR DNA in complex genomes.


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: 2023 ( Subtotal = -$2,697 )
2023	2019	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	4	10/28/2022	NON-COMPETING CONTINUATION	-$2,697
														Subtotal = -$2,697

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	4	2/18/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $283,016 )
2019	2019	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	4	4/2/2019	NON-COMPETING CONTINUATION	$283,016
														Subtotal = $283,016

Issue Date FY: 2018 ( Subtotal = $284,480 )
2018	2018	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	3	4/23/2018	NON-COMPETING CONTINUATION	$284,480
														Subtotal = $284,480

Issue Date FY: 2017 ( Subtotal = $285,842 )
2017	2017	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	001	2	8/7/2017	NON-COMPETING CONTINUATION	$28,585
2017	2017	FLORIDA STATE UNIVERSITY, THE	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	2	4/25/2017	NON-COMPETING CONTINUATION	$257,257
														Subtotal = $285,842

Issue Date FY: 2016 ( Subtotal = $287,108 )
2016	2016	Florida State University	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	1	8/1/2016	NEW	$287,108
														Subtotal = $287,108

Grand Total All Awards = $1,137,749

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Exploring the contribution of large tandem repeat DNA to the organization and maintenance of the inactive X chromosome

Award Number: R01GM117003

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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