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Transcriptional control by autism associated H3K9 methylation regulators during human neurogenesis

Award Number: R01MH139528
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/10/2026
PERIOD OF PERFORMANCE END DATE: 12/31/2030

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Transcriptional control by autism associated H3K9 methylation regulators during human neurogenesis - Project Summary Mutations that reduce or alter the activity of repressive chromatin modifiers are frequent causes of neurodevelopmental disorders. The inaccessibility of the developing and the dynamic nature of neurogenesis so far have prevented an adequate understanding of how molecular pathologies arise downstream of the loss of specific chromatin regulators. This knowledge gap represents a hurdle for developing therapeutic interventions for neurodevelopmental disease. This proposal aims to combine targeted protein depletion with highly efficient directed differentiation regimens for human pluripotent stem cells to dissect gene regulatory functions of the autism-associated chromatin repressor EHMT1 during human cortical neurogenesis. Based on the extensive characterization of a novel, multipurpose (degradation/immunoprecipitation/visualization) degron allele, we hypothesize that interactions with cell type-specific co-factors allow EHMT1 to control the expression of stage- specific target genes during neurogenesis, resulting in the accumulation of molecular alterations and cortical neuron (CN) dysfunction when EHMT1 is lost from early development onwards. To systematically test this hypothesis, we will first determine whether molecular alterations caused by EHMT1 deficiency from earlier stages of neurogenesis onwards accumulate in CNs and to what degree dysregulated gene loci and CN function remain responsive to restoring physiological EHMT1 levels (Aim 1). We will then combine genomics, proteomics, and genetic approaches to identify how EHMT1, together with candidate recruiters and co-factors, regulates distinct gene loci at specific stages of cortical neurogenesis (Aim 2). Finally, we will expand our degron approach to dissect the functional interplay of different autism-associated H3K9 methylation regulators during human neurogenesis to identify interactions between these proteins that could be clinically exploited (Aim 3). Our experiments will determine currently unknown gene regulatory functions of disease-associated chromatin repressors at critical stages of human cortical neurogenesis. By generating mechanistic insight into how deficiencies of EHMT1 and other H3K9 methylation regulators introduce molecular pathologies in CNs, we anticipate revealing new opportunities for therapeutic interventions with specific neurodevelopmental diseases.


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: 2026 ( Subtotal = $800,667 )
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Mental Health Research Grants	000	1	3/10/2026	NEW	$800,667
														Subtotal = $800,667

Grand Total All Awards = $800,667

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Transcriptional control by autism associated H3K9 methylation regulators during human neurogenesis

Award Number: R01MH139528

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/10/2026

PERIOD OF PERFORMANCE END DATE: 12/31/2030

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