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The stage-specific regulation of ameloblastin and enamelin by the distinct nuclear factors

Award Number: R01DE027076
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/06/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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The stage-specific regulation of ameloblastin and enamelin by the distinct nuclear factors - Abstract Cell identity is largely determined by specific epigenetic landscapes and transcriptional networks. Ameloblast is the only epithelial cell that can generate calcified tissue during development. The initial phase of ameloblast differentiation becomes apparent with the transition from low columnar epithelial cells, known as pre-ameloblasts (PABs), to tall columnar secretory ameloblasts (SABs). It is the SABs that synthesize and deposit unique enamel matrix proteins (EMPs), which scaffold the formation of the organic enamel matrix. These EMPs template the assembly of hydroxyapatites, ultimately occupying the matrix and creating the hardest tissue in the human body. To bioengineer enamel, a tissue that lacks regenerative capacity, a thorough comprehension of the transcriptional regulation of ameloblasts is essential. Specifically, we need to grasp how cells construct their transcriptional programs to facilitate the transition from PABs to SABs. Building upon this foundation, we identified the distinctive temporal expression profile of chromatin organizer, special AT-rich binding protein 1 (SATB1), and have been exploring its indispensable role in orchestrating the transition from pre-ameloblasts (PABs) to secretory ameloblasts (SABs). SATB1 governs the establishment of polarity in secretory ameloblasts (SABs), the secretion of enamel matrix (ECM) proteins, and the structural integrity of the enamel matrix. We also found that ablation of SATB1, highly expressed in PABs, repressed H3K27ac level and Ambn & Enam transcription in SABs. Ameloblastin (Ambn) and enamelin (Enam) encode the major EMPs co-upregulated in SABs and then co-downregulated MABs advance. Our organ culture showed that elevated histone acetylation upregulated Ambn & Enam. An enhancer and base unpairing region (BUR, selective SATB1 DNA binding site) have been predicted in the vicinity of Ambn & Enam gene loci. To further understand the roles of SATB1 in establishing SAB gene transcriptional program and to overcome the low survival rate observed in global SATB1 knock-out mouse lines, we generated additional mouse lines: Satb1 cKO, achieved by crossing K14 Cre with Satb1fl/fl, and Satb1BUR-/-, accomplished by targeted deletion of the SATB1 DNA binding site within Ambn & Enam gene cluster. To address the overarching hypothesis stated in the parental R01, which suggests SATB1 organizes chromatin conformation and poises a transcriptional complex to upregulate Ambn & Enam to advance PABs to SABs, we propose additional experiments in this diversity supplement to complement the original specific aim 1. In alignment with the parental grant, we're conducting chromatin openness profiling, initially targeting the gene loci housing ameloblastin and enamelin. Our investigation spans conditions with or without SATB1, or where SATB1 cannot bind to the BUR site near the ameloblastin/enamelin gene cluster. We're utilizing enamel organ cells and ATAC-seq to achieve this. In further pursuit, we will explore the prospect of employing single cells as input materials for ATAC-seq analyses.


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: 2025 ( Subtotal = $69,982 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	7	12/19/2024	SUPPLEMENT FOR EXPANSION	$69,982
														Subtotal = $69,982

Issue Date FY: 2024 ( Subtotal = $599,626 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	002	7	8/27/2024	NON-COMPETING CONTINUATION	$502,968
2024	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	6	3/13/2024	COMPETING CONTINUATION	$282,855
2024	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	5	11/8/2023	NON-COMPETING CONTINUATION	-$186,197
														Subtotal = $599,626

Issue Date FY: 2023 ( Subtotal = $479,957 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	6	9/6/2023	COMPETING CONTINUATION	$479,957
														Subtotal = $479,957

Issue Date FY: 2021 ( Subtotal = $376,438 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	5	6/24/2021	NON-COMPETING CONTINUATION	$376,438
														Subtotal = $376,438

Issue Date FY: 2020 ( Subtotal = $376,438 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	4	6/15/2020	NON-COMPETING CONTINUATION	$376,438
														Subtotal = $376,438

Issue Date FY: 2019 ( Subtotal = $376,438 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	3	6/12/2019	NON-COMPETING CONTINUATION	$376,438
														Subtotal = $376,438

Issue Date FY: 2018 ( Subtotal = $376,438 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	2	6/6/2018	NON-COMPETING CONTINUATION	$376,438
														Subtotal = $376,438

Issue Date FY: 2017 ( Subtotal = $376,438 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	1	6/21/2017	NEW	$376,438
														Subtotal = $376,438

Grand Total All Awards = $3,031,755

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The stage-specific regulation of ameloblastin and enamelin by the distinct nuclear factors

Award Number: R01DE027076

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/06/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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