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Sox Proteins Modulate Genomic Specificity of B-catenin Regulated Transcription in the Developing Gut

Award Number: R01DK123092
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/ABSTRACT This proposal will test the hypothesis that SOX transcription factors (TFs) modulate the genomic specificity of Wnt/Beta-catenin (BCAT) mediated transcription in early gut development and determine the underlying molecular mechanisms. Wnt signaling regulates gene expression in digestive system development, homeostasis and disease, where it is an important therapeutic target. While the core Wnt transcriptional machinery is well studied, how cell-specific target genes are selected remains one of the most important unresolved issues in the field. Current dogma is that canonical Wnt stabilizes cytoplasmic BCAT, which translocates to the nucleus and interacts with one of four TCF/LEF HMG-box TFs to stimulate transcription. However, all TCFs bind to nearly identical consensus sites indicating they alone cannot account for the diversity of transcriptional responses. Using the complementary advantages of Xenopus embryos and differentiating human pluripotent stem cells (hPSC), we have accumulated compelling evidence that SOX HMG-box TFs modulate the genomic specificity of Wnt/BCAT-mediated transcription during early gut development. Our preliminary ChIP-seq data and functional analyses suggests that different SOX TFs can recruit BCAT to distinct enhancers in a tissue specific manner. On some enhancers SOX and BCAT synergistically activate transcription independent of TCFs. Other enhancers appear to be co-occupied by SOX, BCAT and TCFs, suggesting tertiary complexes where SOX and TCF might cooperate or compete to bind DNA and BCAT to activate or represses transcription. These data suggest novel regulatory mechanisms and indicate that SOXs may be wide-spread unappreciated factors regulating Wnt responses. We propose to test this hypothesis with the following aims: Aim 1: Test the hypothesis that SOXs regulate the genomic recruitment of BCAT to lineage specific enhancers. Aim 2: Determine how Sox17 and Bcat coregulate Wnt-responsive enhancers to control spatially restricted transcription in the embryo. Aim 3: Determine the biochemical mechanisms by which SOX-BCAT-TCF complexes interact on DNA. These studies will reveal the SOX-BCAT regulated GRN of gut development and provide a new paradigm for how cell-specific Wnt-mediated transcription is regulated in development and disease.


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 = $461,728 )
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/15/2023	NON-COMPETING CONTINUATION	$461,728
														Subtotal = $461,728

Issue Date FY: 2023 ( Subtotal = $557,134 )
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	1/25/2023	NON-COMPETING CONTINUATION	$55,714
2023	2023	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/15/2022	NON-COMPETING CONTINUATION	$501,420
														Subtotal = $557,134

Issue Date FY: 2022 ( Subtotal = $557,134 )
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/30/2022	NON-COMPETING CONTINUATION	$55,714
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/14/2021	NON-COMPETING CONTINUATION	$501,420
														Subtotal = $557,134

Issue Date FY: 2021 ( Subtotal = $557,134 )
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/14/2021	NEW	$557,134
														Subtotal = $557,134

Grand Total All Awards = $2,133,130

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Sox Proteins Modulate Genomic Specificity of B-catenin Regulated Transcription in the Developing Gut

Award Number: R01DK123092

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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