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Role of the Rett Syndrome-causing gene MeCP2 in 3D chromosomal organization and rescue of cellular disease phenotypes

Award Number: R00MH113813
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Modified Project Summary/Abstract Section As an NIH Pathway to Independence K99/R00 awardee, I am moving to Columbia University Medical Center to start my research laboratory as a principle investigator for the R00 phase. Rett syndrome (RTT) is an X-linked postnatal progressive neurodevelopmental disorder associated with severe mental disability and autism-like syndromes. The disease is caused by loss-of-function mutations of the DNA binding protein MeCP2 (Methyl CpG-binding Protein 2) in the X chromosome and represents the second most common cause of intellectual disability in females. Loss of MeCP2 leads to expression changes in thousands of genes, compromises the majority of brain cells and circuits, and dysregulates all neurotransmitter systems. However, how MeCP2 can act as a global repressor of gene activity as well as an activator for gene expression remains an open question in the field. Microcephaly (the reduction in brain size) has been documented as a hallmark of RTT, and analysis of hESC/iPSC-derived RTT neurons showed a reduced soma size as well. Our preliminary studies on human RTT mutant neurons showed a panel of cellular phenotypes including reduced soma size, impaired electrical properties, and defects in chromosomal structures. Therefore, we hypothesized that MeCP2 is involved in the organization of 3D chromosomal landscape contributing to the regulation of gene expression and subsequent neurobiology. We demonstrated that MeCP2 proteins form dynamic liquid-like condensates at the heterochromatic regions and concentrate heterochromatic factor HP1a but not components of active transcription in the nucleus. This condensate property of MeCp2 contributes to the compartmentation of 3D genome and the regulation of transcription machinery (Aim 1, K99 phase). Then we found that the intrinsically disordered region-2 (IDR-2) of MeCP2 protein mediates the formation of heterochromatin condensate. A common RTT mutant MeCP2-R168X lacking IDR-2 fails to form heterochromatin condensates to concentrate the heterochromatic factor and causes defects in the transcription regulation, providing a molecular mechanism of MeCP2-mediated 3D chromosomal organization (Aim 2, K99 phase). Development of RTT-like symptoms in mice can be reversed in RTT adult animals following the restoration of MeCP2 expression. As most female RTT patients still carry a wild type allele of MeCP2 subject to the random X-chromosome inactivation (XCI), it will be of therapeutic benefit if the wild type allele of MeCp2 in the inactive X chromosome (Xi) can be reactivated. We developed a DNA methylation editing tool by fusion of a catalytically inactive Cas9 with Tet1/Dnmt3a. Recently we expanded this toolbox to manipulate other epigenetic modifications including histone acetylation and DNA looping. We will use these tools to reverse the RTT phenotypes via reactivation of the wild type MECP2 allele on the Xi (Aim 3, R00 phase).This project will fill the gaps in our knowledge of MeCP2 function in the organization of 3D chromosomal structure and test the novel therapeutic approach to reverse RTT phenotypes.


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: 2024 ( Subtotal = -$394 )
2024	2022	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	5	11/30/2023	NON-COMPETING CONTINUATION	-$394
														Subtotal = -$394

Issue Date FY: 2023 ( Subtotal = -$31,457 )
2023	2020	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	3	5/22/2023	EXTENSION WITH OR WITHOUT FUNDS	-$31,457
														Subtotal = -$31,457

Issue Date FY: 2022 ( Subtotal = $249,000 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	001	5	4/27/2022	NON-COMPETING CONTINUATION	$24,901
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	5	2/1/2022	NON-COMPETING CONTINUATION	$224,099
														Subtotal = $249,000

Issue Date FY: 2021 ( Subtotal = $242,612 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	4	2/3/2021	NON-COMPETING CONTINUATION	$242,612
														Subtotal = $242,612

Issue Date FY: 2020 ( Subtotal = $306,037 )
2020	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	003	3	5/28/2020	EXTENSION WITH OR WITHOUT FUNDS	$31,457
2020	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	001	3	4/7/2020	EXTENSION WITH OR WITHOUT FUNDS	$0
2020	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	002	3	5/8/2020	EXTENSION WITH OR WITHOUT FUNDS	$31,457
2020	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	3	3/20/2020	EXTENSION WITH OR WITHOUT FUNDS	$243,123
														Subtotal = $306,037

Grand Total All Awards = $765,797

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Role of the Rett Syndrome-causing gene MeCP2 in 3D chromosomal organization and rescue of cellular disease phenotypes

Award Number: R00MH113813

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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