PUBLICATION

FoxH1 represses miR-430 during early embryonic development of zebrafish via non-canonical regulation

Authors
Fischer, P., Chen, H., Pacho, F., Rieder, D., Kimmel, R.A., Meyer, D.
ID
ZDB-PUB-190801-19
Date
2019
Source
BMC Biology   17: 61 (Journal)
Registered Authors
Chen, Hao, Fischer, Patrick, Kimmel, Robin, Meyer, Dirk, Pacho, Frederic
Keywords
Chromatin folding, FoxH1, Gastrulation, MZT, Nodal signaling, miR-430
Datasets
GEO:GSE133990
MeSH Terms
  • Animals
  • Embryo, Nonmammalian/metabolism
  • Embryonic Development/genetics*
  • Forkhead Transcription Factors/genetics*
  • Forkhead Transcription Factors/metabolism
  • Gene Expression Regulation, Developmental*
  • MicroRNAs/genetics*
  • MicroRNAs/metabolism
  • Zebrafish/genetics*
  • Zebrafish/growth & development*
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
PubMed
31362746 Full text @ BMC Biol.
Abstract
FoxH1 is a forkhead transcription factor with conserved key functions in vertebrate mesoderm induction and left-right patterning downstream of the TGF-beta/Nodal signaling pathway. Binding of the forkhead domain (FHD) of FoxH1 to a highly conserved proximal sequence motif was shown to regulate target gene expression.
We identify the conserved microRNA-430 family (miR-430) as a novel target of FoxH1. miR-430 levels are increased in foxH1 mutants, resulting in a reduced expression of transcripts that are targeted by miR-430 for degradation. To determine the underlying mechanism of miR-430 repression, we performed chromatin immunoprecipitation studies and overexpression experiments with mutant as well as constitutive active and repressive forms of FoxH1. Our studies reveal a molecular interaction of FoxH1 with miR-430 loci independent of the FHD. Furthermore, we show that previously described mutant forms of FoxH1 that disrupt DNA binding or that lack the C-terminal Smad Interaction Domain (SID) dominantly interfere with miR-430 repression, but not with the regulation of previously described FoxH1 targets.
We were able to identify the distinct roles of protein domains of FoxH1 in the regulation process of miR-430. We provide evidence that the indirect repression of miR-430 loci depends on the connection to a distal repressive chromosome environment via a non-canonical mode. The widespread distribution of such non-canonical binding sites of FoxH1, found not only in our study, argues against a function restricted to regulating miR-430 and for a more global role of FoxH1 in chromatin folding.
Genes / Markers
Figures
Figure Gallery
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes