Saturday, December 2, 2023 12/2/2023

Regulation of intestinal genes by CDX2 and other tissue-restricted transcription factors

Award Number: R01DK082889
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Description Common disorders of the digestive tract, such as Inflammatory Bowel Disease, colorectal cancer and Barrett's esophagus reflect profound epithelial dysfunction and gene dysregulation. Improved treatments require better understanding of the basis for intestine-specific gene control. Certain transcription factors (TFs) – CDX2, HNF4 and HNF1 – act at the distant enhancers of genes that define gut epithelial identity and function, but mechanisms of enhancer assembly, specificity, and activity are not well understood. Nor is it known how chromatin and TF dynamics in gut endoderm allow the emergence of distinctive digestive epithelia. This proposal addresses some of these fundamental questions in mouse intestinal cells in vivo. Among thousands of cis-elements that control intestinal genes, we identify a new class of tissue-specific enhancers that require CDX2 to exclude the repressive histone mark H3K27me3 from large genomic domains; H3K27me3 was not previously implicated at distant enhancers in adult tissues. These findings ascribe a novel, unexpected function for CDX2 at `anti-repressive' Type 1A enhancers that control the most quantitatively vulnerable genes in Cdx2-/- villus cells. Specific Aim 1 addresses the requirements and mechanisms of these novel enhancers. We propose genetic and biochemical experiments to test two central hypotheses: (a) that ~500 key intestinal loci are particularly susceptible to repression by virtue of extensive local deposition of H3K27me3, and (b) that CDX2 recruits the specific H3K27 demethylases KDM6A/B to oppose that locus-wide effect. We will use Eed-/- intestines, which lack methylated H3K27, to determine whether this feature is causally repressive and to attempt rescue of the genes most perturbed in Cdx2-/- intestines. Because Type 1A enhancers show a large difference in H3K27me3 levels between enterocyte progenitors in intestinal crypts and terminally mature enterocytes along the villi, we propose studies to test the hypothesis that this repressive mark limits high expression of enterocyte genes in replicating crypt cells. Specific Aim 2 considers the developmental origins and determinants of intestinal enhancers and asks why certain genomic domains acquire tissue-specific H3K27me3. This Aim builds on our discovery that nascent enhancers for all digestive epithelia are initially accessible throughout the early endoderm and that tissue-specific sites later strengthen in each organ while inappropriate enhancers are shut down. We will test the hypothesis that regions dependent on Type 1A enhancers in the adult intestine are the vestiges of enhancers that were used in development. We will also test the hypotheses that: (a) unless regional TFs reinforce open endodermal chromatin, enhancers shut down in a rostral-caudal wave, and (b) the state of chromatin at any time determines how the developing intestine responds to absence of CDX2. This proposal thus applies innovative state-of-the-art approaches to pursue exciting discoveries and address fundamental questions about intestinal gene regulation in vivo.


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	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	11	10/26/2023	COMPETING CONTINUATION	$45,190
2024	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	10/26/2023	NON-COMPETING CONTINUATION	-$45,190


Issue Date FY: 2023 ( Subtotal = $372,621 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	11	2/22/2023	COMPETING CONTINUATION	$372,621
2023	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	2/13/2023	NON-COMPETING CONTINUATION	$0


Issue Date FY: 2021 ( Subtotal = $382,248 )
2021	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	7/22/2021	NON-COMPETING CONTINUATION	$382,248


Issue Date FY: 2020 ( Subtotal = $382,248 )
2020	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	7/23/2020	NON-COMPETING CONTINUATION	$382,248


Issue Date FY: 2019 ( Subtotal = $382,248 )
2019	2019	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	7/16/2019	NON-COMPETING CONTINUATION	$382,248


Issue Date FY: 2018 ( Subtotal = $382,248 )
2018	2018	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	7/17/2018	NON-COMPETING CONTINUATION	$382,248
2018	2014	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	1/19/2018	NON-COMPETING CONTINUATION	$0


Issue Date FY: 2017 ( Subtotal = $382,248 )
2017	2017	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	8/1/2017	COMPETING CONTINUATION	$382,248


Issue Date FY: 2016 ( Subtotal = $0 )
2016	2014	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	8/9/2016	NON-COMPETING CONTINUATION	$0


Issue Date FY: 2014 ( Subtotal = $357,029 )
2014	2014	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	8/14/2014	NON-COMPETING CONTINUATION	$357,029


Issue Date FY: 2013 ( Subtotal = $344,532 )
2013	2013	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/8/2013	NON-COMPETING CONTINUATION	$344,532


Issue Date FY: 2012 ( Subtotal = $357,029 )
2012	2012	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	8/31/2012	NON-COMPETING CONTINUATION	$357,029


Issue Date FY: 2011 ( Subtotal = $357,029 )
2011	2011	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/18/2011	NON-COMPETING CONTINUATION	$357,029


Issue Date FY: 2010 ( Subtotal = $426,232 )
2010	2010	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/1/2010	NEW	$426,232


Grand Total All Awards = $4,125,712

Sum of Action Amount is $4,125,712;

Grand Total = $4,125,712

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Regulation of intestinal genes by CDX2 and other tissue-restricted transcription factors

Award Number: R01DK082889

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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