Molecular mechanism of HNF-1A-mediated HNF4A gene regulation and promoter-driven HNF4A-MODY diabetes

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064203%3A_____%2F24%3A10481141" target="_blank" >RIV/00064203:_____/24:10481141 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11130/24:10481141

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=CfKg2GXUWn" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=CfKg2GXUWn</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1172/jci.insight.175278" target="_blank" >10.1172/jci.insight.175278</a>

Result language

angličtina

Original language name

Molecular mechanism of HNF-1A-mediated HNF4A gene regulation and promoter-driven HNF4A-MODY diabetes

Original language description

Monogenic diabetes is a gateway to precision medicine through molecular mechanistic insight. Hepatocyte nuclear factor 1A (HNF-1A) and HNF-4A are transcription factors that engage in crossregulatory gene transcription networks to maintain glucose-stimulated insulin secretion in pancreatic β cells. Variants in the HNF1A and HNF4A genes are associated with maturity-onset diabetes of the young (MODY). Here, we explored 4 variants in the P2-HNF4A promoter region: 3 in the HNF-1A binding site and 1 close to the site, which were identified in 63 individuals from 21 families of different MODY disease registries across Europe. Our goal was to study the disease causality for these variants and to investigate diabetes mechanisms on the molecular level. We solved a crystal structure of HNF-1A bound to the P2-HNF4A promoter and established a set of techniques to probe HNF-1A binding and transcriptional activity toward different promoter variants. We used isothermal titration calorimetry, biolayer interferometry, x-ray crystallography, and transactivation assays, which revealed changes in HNF-1A binding or transcriptional activities for all 4 P2-HNF4A variants. Our results suggest distinct disease mechanisms of the promoter variants, which can be correlated with clinical phenotype, such as age of diagnosis of diabetes, and be important tools for clinical utility in precision medicine.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30202 - Endocrinology and metabolism (including diabetes, hormones)

Project

<a href="/en/project/NW24-01-00160" target="_blank" >NW24-01-00160: Whole genome sequencing as tool for search of novel variations causing monogenic diabetes and hyperinsulinism</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2024

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

JCI Insight

ISSN

2379-3708

e-ISSN

2379-3708

Volume of the periodical

9

Issue of the periodical within the volume

11

Country of publishing house

US - UNITED STATES

Number of pages

21

Pages from-to

e175278

UT code for WoS article

001244258600001

EID of the result in the Scopus database

2-s2.0-85195625157