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Transcriptional control and enhancer recruitment in mouse and human intestinal secretory differentiation

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 SUMMARY Intestinal secretory (Sec: goblet (Gob), enteroendocrine (EE), Paneth (Pan), and tuft) cells serve vital digestive, metabolic, barrier, and other physiologic functions. Intestinal stem cells (ISCs) replenish both absorptive and Sec epithelial cells, but the origins of Sec diversity and census are largely unknown. Because it has been difficult to isolate and characterize intermediate precursor cell states, much of the current understanding of the mouse and human Sec lineages rests on mouse genetic studies. On morphologic and functional grounds, the four mature Sec cell types are considered distinct and their origins trace to a common ATOH1-expressing crypt progenitor (Sec-Pro), although some mouse EE and tuft –but not Gob or Pan– cells arise in the absence of this Sec-specifying transcription factor (TF). Cell fates are generally dictated by cell- specific cis-regulatory elements (CREs – mainly enhancers) that drive particular transcriptional programs under the direction of cell-restricted TFs. To understand how primitive Sec-Pro execute subsequent CRE and cell fate decisions, we have developed two parallel and powerful experimental systems: (1) Capture of labeled early mouse Sec derivatives in vivo for deep characterization of gene and enhancer activity at single- cell resolution, and (2) Differentiation of 2D human ISC-like cells in vitro along the full Sec lineage. Both models yield large numbers of multi- and bi-potential precursors, hence allowing original mechanistic insights into the corresponding transcriptional and CRE states. Our three Specific Aims integrate findings from the two parallel models to decipher the epigenetic basis and regulatory TF logic of mouse and human Sec cell differentiation. Aim 1 uses mRNA and open-chromatin profiles of precursor and descendant Sec cells within a differentiation continuum to characterize the salient features of specific intermediate states, map previously unknown TF-driven transitions, distinguish cell-autonomous from -extrinsic factors, and thus derive a unifying model for mammalian Sec lineage diversity. Considered in the light of scattered published findings, our preliminary data suggest that Gob and Pan are not genuinely distinct cell types, but different versions of a versatile Sec end-product where specific local signals act on the same complement of open chromatin to drive Gob or Pan features. Aim 2 applies a suite of in vitro and in vivo experiments to test specific hypotheses that epidermal growth factor (EGF) and especially canonical Wnt signaling favor the Pan state, while bone morphogenetic protein (BMP) signaling drives the Gob state. We will examine how alternative recruitment of Gob- or Pan-selective CREs by specific signaling pathways might underlie these fluid cell states. Aim 3 uses gain- and loss-of-function strategies to address previously challenging questions about TF-driven specification of human Sec, especially EE and tuft, cells. Overall, a particular strength of this proposal is the deeply mechanistic investigation of cell-specific CREs and TFs that together dictate interim and final cell potential in the murine and human Sec lineage.


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 = $357,716 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	12	5/10/2024	NON-COMPETING CONTINUATION	$22,357
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	12	2/15/2024	NON-COMPETING CONTINUATION	$335,359
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
														Subtotal = $357,716

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
														Subtotal = $372,621

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
														Subtotal = $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
														Subtotal = $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
														Subtotal = $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
														Subtotal = $382,248

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
														Subtotal = $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
														Subtotal = $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
														Subtotal = $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
														Subtotal = $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
														Subtotal = $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
														Subtotal = $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
														Subtotal = $426,232

Grand Total All Awards = $4,483,428

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Transcriptional control and enhancer recruitment in mouse and human intestinal secretory differentiation

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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