Haploinsufficiency of RREB1 causes a Noonan-like RASopathy via epigenetic reprogramming of RAS-MAPK pathway genes

Oliver A Kent,Yoshinori Matsumoto,Kevin R Brown,Helen E Burston,Keith Dadson,Justin Cowen,Brian Raught,Daniel D De Carvalho,Napoleon Law,Ren Sun ,José La Rose ,Estelle Laurent ,Étienne Coyaud ,Charles A Ishak ,Jonathan St-Germain,Filio Billia,Sujun Chen,Manipa Saha,Aaryn Montgomery-Song,Peter Kannu,Housheng Hansen He,Robert Rottapel

doi:10.1038/s41467-020-18483-9

Abstract

RAS-MAPK signaling mediates processes critical to normal development including cell proliferation, survival, and differentiation. Germline mutation of RAS-MAPK genes lead to the Noonan-spectrum of syndromes. Here, we present a patient affected by a 6p-interstitial microdeletion with unknown underlying molecular etiology. Examination of 6p-interstitial microdeletion cases reveals shared clinical features consistent with Noonan-spectrum disorders including short stature, facial dysmorphia and cardiovascular abnormalities. We find the RAS-responsive element binding protein-1 (RREB1) is the common deleted gene in multiple 6p-interstitial microdeletion cases. Rreb1 hemizygous mice display orbital hypertelorism and cardiac hypertrophy phenocopying the human syndrome. Rreb1 haploinsufficiency leads to sensitization of MAPK signaling. Rreb1 recruits Sin3a and Kdm1a to control H3K4 methylation at MAPK pathway gene promoters. Haploinsufficiency of SIN3A and mutations in KDM1A cause syndromes similar to RREB1 haploinsufficiency suggesting genetic perturbation of the RREB1-SIN3A-KDM1A complex represents a new category of RASopathy-like syndromes arising through epigenetic reprogramming of MAPK pathway genes.

Highlights

RAS-MAPK signaling mediates processes critical to normal development including cell proliferation, survival, and differentiation
Our data demonstrate that RAS-responsive element binding protein-1 (RREB1) forms a transcriptional repressive complex together with SIN3A and KDM1A which normally leads to transcriptional inactivation of MAPK signaling components
We provide genetic and biochemical evidence that dysregulation of Fgfr[4], Hras and Map2k2 in the heart of Rreb[1] heterozygous mice is deleterious leading to a cardiomyopathy that is reminiscent of the phenotype observed in Noonan-like RASopathies

Summary

Introduction

RAS-MAPK signaling mediates processes critical to normal development including cell proliferation, survival, and differentiation. We find the RAS-responsive element binding protein-1 (RREB1) is the common deleted gene in multiple 6p-interstitial microdeletion cases. MAPK pathway regulation and controlled expression of MAPK target genes is essential in mediating diverse physiologic outcomes including cellular transformation, tumorigenesis, developmental disorders, cardiac hypertrophy and heart failure. Germline gain-of and loss-of-function mutations in genes of the RAS-MAPK pathway lead to the Noonan-spectrum of autosomal dominant disorders, a group of malformation syndromes affecting 1 in 1000 individuals[5,6,7]. Rreb[1] haploinsufficiency resembles a RASopathy-like syndrome and leads to sensitization of MAPK signaling in fibroblast and cardiac cells. RREB1 recruits SIN3A and KDM1A to an RRE in target promoters in human and murine cells to control histone H3K4 methylation of MAPK pathway genes

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Results

Conclusion