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Regulation of hepatic microRNA expression by hepatocyte nuclear factor 4 alpha

Hong Lu1, Xiaohong Lei1, Jerry Liu1

  • 1Hong Lu, Xiaohong Lei, Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, United States.

World Journal of Hepatology
|February 21, 2017
PubMed
Abstract

Insights

Hepatocyte nuclear factor 4 alpha (HNF4α) is crucial for regulating liver-specific microRNAs, impacting gene expression and epigenetic maintenance. This study reveals HNF4α

Area of Science:

  • Hepatology and molecular biology
  • Epigenetics and gene regulation
  • MicroRNA biology

Background:

  • Hepatocyte nuclear factor 4 alpha (HNF4α) is a key transcription factor in liver function.
  • MicroRNAs (miRNAs) are critical regulators of gene expression.
  • The precise role of HNF4α in miRNA regulation within the liver remains incompletely understood.

Purpose of the Study:

  • To elucidate the function of HNF4α in controlling the hepatic expression of microRNAs.
  • To investigate the direct and indirect mechanisms by which HNF4α influences miRNA transcription and function.

Main Methods:

  • Comparative analysis of miRNA expression in HNF4α-deficient mice (HNF4α-LivKO) using microarrays and real-time PCR.
  • Bioinformatic analysis of public ChIP-seq data to identify HNF4α and RNA polymerase-II binding sites at miRNA loci.
  • Dual-luciferase reporter assays to assess HNF4α's impact on miRNA promoter activity and miRNA effects on target gene 3'UTRs.

Main Results:

  • HNF4α deficiency led to down-regulation of specific liver-predominant miRNAs, including miR-101, miR-192, miR-193a, miR-194, and miR-802.
  • ChIP-seq analysis confirmed direct HNF4α binding to the promoters of several down-regulated miRNAs, correlating with active transcription marks.
  • Luciferase assays demonstrated HNF4α's activation of miR-101 and miR-194/miR-192 cluster promoters, and identified miR-192 and miR-194 as potential regulators of epigenetic modifiers.

Conclusions:

  • HNF4α is essential for maintaining the basal expression of a subset of liver-enriched miRNAs.
  • HNF4α plays a significant role in post-transcriptional gene regulation and epigenome maintenance in the liver via miRNA regulation.
  • These findings highlight HNF4α as a central regulator linking transcription, miRNA expression, and epigenetic control in hepatocytes.
Keywords:
Hepatocyte nuclear factor 4 alphaHumanKnockoutLiverMicemiR-101miR-122miR-192miR-194miR-802

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