Structural insights into the HNF4 biology

Brice Beinsteiner; Isabelle M L Billas; Dino Moras

doi:10.3389/fendo.2023.1197063

Structural insights into the HNF4 biology

Front Endocrinol (Lausanne). 2023 Jun 19:14:1197063. doi: 10.3389/fendo.2023.1197063. eCollection 2023.

Authors

Brice Beinsteiner^{1

2

3

4}, Isabelle M L Billas^{1

2

3

4}, Dino Moras^{1

2

3

4}

Affiliations

¹ Laboratory IGBMC (Institute of Genetics and of Molecular and Cellular Biology), Centre for Integrative Biology (CBI), Illkirch, France.
² Université de Strasbourg (Unistra), Strasbourg, France.
³ Institut National de la Santé et de la Recherche Médicale (INSERM) U1258, Illkirch, France.
⁴ Centre National de la Recherche Scientifique (CNRS) UMR 7104, Illkirch, France.

Abstract

Hepatocyte Nuclear Factor 4 (HNF4) is a transcription factor (TF) belonging to the nuclear receptor (NR) family that is expressed in liver, kidney, intestine and pancreas. It is a master regulator of liver-specific gene expression, in particular those genes involved in lipid transport and glucose metabolism and is crucial for the cellular differentiation during development. Dysregulation of HNF4 is linked to human diseases, such as type I diabetes (MODY1) and hemophilia. Here, we review the structures of the isolated HNF4 DNA binding domain (DBD) and ligand binding domain (LBD) and that of the multidomain receptor and compare them with the structures of other NRs. We will further discuss the biology of the HNF4α receptors from a structural perspective, in particular the effect of pathological mutations and of functionally critical post-translational modifications on the structure-function of the receptor.

Keywords: DNA Allostery; HNF4; MODY1; hepatocyte nuclear factor 4; nuclear receptors; protein-DNA complexes; structural biology; transcription.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Biology
DNA-Binding Proteins* / genetics
Gene Expression Regulation
Hepatocyte Nuclear Factor 4* / genetics
Hepatocyte Nuclear Factor 4* / metabolism
Humans
Receptors, Cytoplasmic and Nuclear / genetics

Substances

DNA-Binding Proteins
Hepatocyte Nuclear Factor 4
Receptors, Cytoplasmic and Nuclear

Grants and funding

Work in our laboratory is supported by CNRS, INSERM, University of Strasbourg and by the French Infrastructure for Integrated Structural Biology (FRISBI) ANR-10-INSB-05 and Instruct-ERIC, the national research agency ANR MYOGLUCO (ANR-22-CE11-0014-01) and the Ligue Contre le Cancer CCIR Est. This work of the Interdisciplinary Thematic Institute IMCBio, as part of the ITI 2021-2028 program of the University of Strasbourg, CNRS and Inserm, was supported by IdEx Unistra (ANR-10-IDEX-0002).