TY - JOUR

T1 - The H3K4me3/2 histone demethylase RBR-2 controls axon guidance by repressing the actin-remodeling gene wsp-1

AU - Mariani, Luca

AU - Lussi, Yvonne C

AU - Vandamme, Julien

AU - Riveiro, Alba

AU - Salcini, Anna Elisabetta

N1 - © 2016. Published by The Company of Biologists Ltd.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - The dynamic regulation of histone modifications is important for modulating transcriptional programs during development. Aberrant H3K4 methylation is associated with neurological disorders, but how the levels and the recognition of this modification affect specific neuronal processes is unclear. Here, we show that RBR-2, the sole homolog of the KDM5 family of H3K4me3/2 demethylases in Caenorhabditis elegans, ensures correct axon guidance by controlling the expression of the actin regulator wsp-1. Loss of rbr-2 results in increased levels of H3K4me3 at the transcriptional start site of wsp-1, with concomitant higher wsp-1 expression responsible for defective axon guidance. In agreement, overexpression of WSP-1 mimics rbr-2 loss, and its depletion restores normal axon guidance in rbr-2 mutants. NURF-1, an H3K4me3-binding protein and member of the chromatin-remodeling complex NURF, is required for promoting aberrant wsp-1 transcription in rbr-2 mutants and its ablation restores wild-type expression of wsp-1 and axon guidance. Thus, our results establish a precise role for epigenetic regulation in neuronal development by demonstrating a functional link between RBR-2 activity, H3K4me3 levels, the NURF complex and the expression of WSP-1.

AB - The dynamic regulation of histone modifications is important for modulating transcriptional programs during development. Aberrant H3K4 methylation is associated with neurological disorders, but how the levels and the recognition of this modification affect specific neuronal processes is unclear. Here, we show that RBR-2, the sole homolog of the KDM5 family of H3K4me3/2 demethylases in Caenorhabditis elegans, ensures correct axon guidance by controlling the expression of the actin regulator wsp-1. Loss of rbr-2 results in increased levels of H3K4me3 at the transcriptional start site of wsp-1, with concomitant higher wsp-1 expression responsible for defective axon guidance. In agreement, overexpression of WSP-1 mimics rbr-2 loss, and its depletion restores normal axon guidance in rbr-2 mutants. NURF-1, an H3K4me3-binding protein and member of the chromatin-remodeling complex NURF, is required for promoting aberrant wsp-1 transcription in rbr-2 mutants and its ablation restores wild-type expression of wsp-1 and axon guidance. Thus, our results establish a precise role for epigenetic regulation in neuronal development by demonstrating a functional link between RBR-2 activity, H3K4me3 levels, the NURF complex and the expression of WSP-1.

KW - Actins

KW - Alleles

KW - Animals

KW - Axons

KW - Body Patterning

KW - Caenorhabditis elegans

KW - Caenorhabditis elegans Proteins

KW - Catalysis

KW - Chromatin

KW - Chromosomal Proteins, Non-Histone

KW - Epigenesis, Genetic

KW - Gene Expression Regulation, Developmental

KW - Histone Demethylases

KW - Histones

KW - Lysine

KW - Methylation

KW - Microscopy, Fluorescence

KW - Mutation

KW - Neurons

KW - Protein Structure, Tertiary

KW - Retinoblastoma-Binding Protein 2

KW - Signal Transduction

KW - Transgenes

KW - Journal Article

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

U2 - 10.1242/dev.132985

DO - 10.1242/dev.132985

M3 - Journal article

C2 - 26811384

VL - 143

SP - 851

EP - 863

JO - Development

JF - Development

SN - 0950-1991

IS - 5

ER -