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Epigenetic regulation of serotonergic neuron subtype maturation and function by the DNA methyltransferase DNMT3A

Award Number: F31MH145942
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/04/2027
PERIOD OF PERFORMANCE END DATE: 02/03/2028

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Epigenetic regulation of serotonergic neuron subtype maturation and function by the DNA methyltransferase DNMT3A - PROJECT SUMMARY/ABSTRACT The serotonergic neuronal system of the brain comprises diverse subtypes of serotonin (5-hydroxytryptamine, 5-HT)-producing neurons, each modulating different processes ranging from mood to social behavior to autonomic functions. Disruptions in their development are implicated in many disorders, including autism, major depressive disorder, and the sudden infant death syndrome, yet the molecular mechanisms underlying their maturation and functional specialization remain poorly understood. Epigenetic regulation through DNA methylation is thought to be crucial for defining stable neuronal identities during early postnatal life. Our preliminary single-cell transcriptomic data from postnatal mouse brain reveal that Dnmt3a mRNA is highly upregulated during early postnatal development, with timing that differs across serotonergic neuron subtypes. DNMT3A is the sole enzyme that deposits the mCA methylation mark uniquely enriched in neurons, positioning it as a gatekeeper of serotonergic neuronal maturation. Its role in serotonergic neurons is unknown. This project investigates how DNMT3A establishes gene-regulatory programs in serotonergic neuron subtypes. To identify transcriptomic and chromatin changes in serotonergic neuron subtypes, as well as alterations in subtype number and organization, following loss of DNMT3A function (Aim 1), we will use single- nucleus RNA+ATAC multiomic profiling of 5-HTergic neurons from Dnmt3aPet1-CKO versus control wild-type mice. Using additional mouse cohorts of these genotypes in Aim 2, we will map genome-wide DNA methylation patterns and DNMT3A occupancy in serotonergic neurons using bisulfite sequencing and CUT&RUN, interpreting transcriptomic changes within the context of upstream chromatin mechanisms. In Aim 3, we will test how loss of DNMT3A in serotonergic neurons alters social, anxiety-related, and hedonic behaviors, relating these findings to the molecular changes identified. These studies will elucidate how DNA methylation programs direct serotonergic neuron subtype identities and how their disruption leads to long-term behavioral consequences. This work may position DNMT3A as a therapeutic target for disorders rooted in serotonergic dysfunction. Training under Dr. Susan Dymecki at Harvard Medical School will provide rigorous mentorship in epigenetics, behavioral neuroscience, and bioinformatics, preparing me for an independent research career at the intersection of epigenetics and brain development.


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 = $43,325 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	1	8/6/2026	NEW	$43,325
														Subtotal = $43,325

Grand Total All Awards = $43,325

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Epigenetic regulation of serotonergic neuron subtype maturation and function by the DNA methyltransferase DNMT3A

Award Number: F31MH145942

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/04/2027

PERIOD OF PERFORMANCE END DATE: 02/03/2028

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