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Identifying Epigenetic, Chromatin, and Transcriptomic landscapes to Improve SCNT Development in an Animal Model

Award Number: R01HD095833
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Identifying Epigenetic, Chromatin, and Transcriptomic landscapes to Improve SCNT Development in an Animal Model - PROJECT SUMMARY Somatic cell nuclear transfer (SCNT) allows for the creation of genetically identical animals for agricultural purposes, and is a powerful tool for production of genetically engineered animals for biomedical applications and generation of patient-specific embryonic stem cells (SCNT-ESCs) for therapeutics. However, the low efficiency of full term development limits its wide-spread use and practical utility. The fundamental problem is how the egg incompletely reprograms a somatic donor nucleus. The overall objectives of the current proposal are outlined in the two Specific Aims : 1) Identify epigenetic, chromatin, and transcriptomic landscapes in in vitro fertilized (IVF) embryos and then elucidate how SCNT embryos deviate from this developmental paradigm; and 2) Establish and test new approaches to correct reprogramming defects and improve SCNT development both in preimplantation and postimplantation embryos. We have created high- quality open chromatin maps for carefully-staged IVF and SCNT bovine embryos and leveraged cutting-edge single-cell open chromatin profiling to clarify intra- and inter-embryo heterogeneity in chromatin reprogramming. These maps allow us to interrogate, for the first time, how specific regions of the genome open and close during normal preimplantation development, and how SCNT embryos deviate from this paradigm. Our preliminary data clearly indicate early cleavage staged SCNT embryos do not establish open chromatin properly, and implicate an important contributor to EGA, a transcription factor (TF) DUX, as a major deficiency in SCNT embryos. We hypothesize that failures in chromatin reprogramming during SCNT preimplantation development manifest later in postimplantation development, and that targeted intervention using TF expression or preimplantation screening will improve SCNT developmental success. Aim 1 consists of three subaims: 1.1. Determine sex-specific SCNT open chromatin regions that deviate from IVF embryos, or exhibit sex-specificity; 1.2. Identify somatic memory in SCNT embryos that is resistant to reprogramming using DNA methylation profiling; and 1.3. Identify gene expression differences between SCNT and IVF blastocysts and evaluate if they are biased towards ICM or TE lineages. Based on these data, we will use bioinformatic analyses to identify additional TFs/regulators for further mechanistic dissection. In Aim 2, three subaims will be tested: 2.1. if ectopic enforcement of EGA (using DUX and other TFs) can reactivate the EGA program in cultured fibroblasts; 2.2. If targeted activation of the EGA network in SCNT embryos using TF or TF combinations (from 2.1) would improve reprogramming and facilitate their development and 2.3. If single- cell biopsy and open chromatin profiling at early stages can predict developmental outcomes of both IVF and SCNT embryos. These goals will improve the efficiency of generation of agricultural and biomedical animal models and establish strategies and insights for human clinical applications.


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 = -$72,548 )
2026	2023	UTAH STATE UNIVERSITY	1000 OLD MAIN HL	LOGAN	UT	84322	CACHE	USA	Child Health and Human Development Extramural Research	000	5	11/24/2025	NON-COMPETING CONTINUATION	-$72,548
														Subtotal = -$72,548

Issue Date FY: 2023 ( Subtotal = $373,636 )
2023	2023	UTAH STATE UNIVERSITY	1000 OLD MAIN HILL	LOGAN	UT	84322	CACHE	USA	Child Health and Human Development Extramural Research	000	5	5/16/2023	NON-COMPETING CONTINUATION	$373,636
														Subtotal = $373,636

Issue Date FY: 2022 ( Subtotal = $417,067 )
2022	2022	UTAH STATE UNIVERSITY	1000 OLD MAIN HILL	LOGAN	UT	84322	CACHE	USA	Child Health and Human Development Extramural Research	000	4	5/18/2022	NON-COMPETING CONTINUATION	$417,067
														Subtotal = $417,067

Issue Date FY: 2021 ( Subtotal = $458,992 )
2021	2021	UTAH STATE UNIVERSITY	1000 OLD MAIN HILL	LOGAN	UT	84322	CACHE	USA	Child Health and Human Development Extramural Research	000	3	5/17/2021	NON-COMPETING CONTINUATION	$458,992
														Subtotal = $458,992

Issue Date FY: 2020 ( Subtotal = $397,785 )
2020	2020	UTAH STATE UNIVERSITY	1000 OLD MAIN HILL	LOGAN	UT	84322	CACHE	USA	Child Health and Human Development Extramural Research	000	2	6/9/2020	NON-COMPETING CONTINUATION	$397,785
														Subtotal = $397,785

Issue Date FY: 2019 ( Subtotal = $436,929 )
2019	2019	UTAH STATE UNIVERSITY	1000 OLD MAIN HILL	LOGAN	UT	84322	CACHE	USA	Child Health and Human Development Extramural Research	000	1	8/30/2019	NEW	$436,929
														Subtotal = $436,929

Grand Total All Awards = $2,011,861

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Identifying Epigenetic, Chromatin, and Transcriptomic landscapes to Improve SCNT Development in an Animal Model

Award Number: R01HD095833

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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