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Establishment and visualization of nuclear architecture at the onset of mammalian development

Award Number: U01DK127391
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/16/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Establishment and visualization of nuclear architecture at the onset of mammalian development - Project Summary/Abstract “Establishment and visualization of nuclear architecture at the onset of mammalian development” Nuclear organization is a key feature of our epigenome. The way in which our DNA is folded into the cell nucleus can affect gene expression and determine cellular identity, but it can also regulate recombination and genome instability. Indeed, the disruption of key elements underlying the architecture of the nucleus, such as Topologically-Associated Domain (TAD) boundaries, has been shown to be the cause of genetically inherited diseases in some instances. How nuclear organization is first established after fertilization in mammals is largely unknown. In particular, the lack of approaches to observe in real time the different layers of nuclear organization has been a barrier for the full understanding of the dynamics and the impact of nuclear organization in vivo. Most importantly, the chromatin and structural pathways that regulate the initial folding of our genome into the nucleus as well as the impact of the resulting genome organization for key developmental and transcriptional processes in vivo, is largely unknown. We have recently shown that nuclear organization, particularly the association of specific genomic regions to the nuclear lamina, is established de novo in the newly formed embryo immediately after fertilization. Lamina- Associated Domains (LADs) precede the consolidation of TADs and compartments, suggesting that the association with the nuclear lamina may be the first nuclear architectural scaffold and set the framework for nuclear architecture. Here, to fulfill the outstanding need for methodologies to visualize specific chromosome domains, we will establish “LivePaint”, a technology to visualize the fundamental pillars of genome organization and their dynamics in real time (Aim 1). We propose to image the process of establishment of nuclear architecture by applying this tool to the mouse pre-implantation embryo, a full organism amenable to imaging and in which real time dynamics can be studied in their natural context. In parallel, we will deploy low input genomic approaches, such as DamID to identify the regulators of LAD establishment (Aim 2). Finally, using this information, we will perform perturbations to establish the role of LADs in regulating the establishment of nuclear architecture through both imaging and genomics approaches (Aim 3). We will also identify the impact of the disruption to the establishment of nuclear organization in vivo on epigenetic features, such as replication timing and gene expression and ultimately their impact on developmental competence. Through the perturbation and live imaging of the main determinants of nuclear organization in vivo, this proposal will establish the functional dependencies between the different layers of nuclear organization and will reveal their role in cellular function, gene expression and developmental progression at the beginning of mammalian development. The knowledge generated through these Aims will address outstanding challenges for our understanding of how the mammalian genome folds within the nuclear space in a physiological context and will reveal molecular regulators of this process.


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 = $0 )
2024	2023	HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT (GMBH)	INGOLSTAEDTER LANDSTR. 1	OBERSCHLEISSHEIM				DEU	Trans-NIH Research Support	000	4	5/23/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $393,866 )
2023	2023	HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT (GMBH)	INGOLSTAEDTER LANDSTR. 1	OBERSCHLEISSHEIM				DEU	Trans-NIH Research Support	001	4	8/14/2023	NON-COMPETING CONTINUATION	$393,866
2023	2022	HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT (GMBH)	INGOLSTAEDTER LANDSTR. 1	OBERSCHLEISSHEIM				DEU	Trans-NIH Research Support	000	3	8/11/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $393,866

Issue Date FY: 2022 ( Subtotal = $393,866 )
2022	2022	HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT (GMBH)	INGOLSTAEDTER LANDSTR. 1	OBERSCHLEISSHEIM				DEU	Trans-NIH Research Support	000	3	9/13/2022	NON-COMPETING CONTINUATION	$393,866
														Subtotal = $393,866

Issue Date FY: 2021 ( Subtotal = $393,866 )
2021	2021	HELMHOLTZ ZENTRUM MUNCHEN DEUTSCHES FORSCHUNGSZENTRUM FUR GESUNDHEIT UND UMWELT (GMBH)	INGOLSTADTER LANDSTR. 1	OBERSCHLEISSHEIM	BAYERN			DEU	Trans-NIH Research Support	000	2	7/23/2021	NON-COMPETING CONTINUATION	$393,866
														Subtotal = $393,866

Issue Date FY: 2020 ( Subtotal = $269,822 )
2020	2020	HELMHOLTZ ZENTRUM MUNCHEN DEUTSCHES FORSCHUNGSZENTRUM FUR GESUNDHEIT UND UMWELT (GMBH)	INGOLSTADTER LANDSTR. 1	OBERSCHLEISSHEIM	BAYERN	85764		DEU	Trans-NIH Research Support	000	1	9/16/2020	NEW	$269,822
														Subtotal = $269,822

Grand Total All Awards = $1,451,420

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Establishment and visualization of nuclear architecture at the onset of mammalian development

Award Number: U01DK127391

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/16/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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