Loss of H3K9
remodelling
methylation
contributes
to
cardiac
hypertrophic
Bernard Thienpont1,2,8, Jan Aronsen3,4,8, Emma Robinson1, Hanneke
Okkenhaug1, Elena Loche1,5, Arianna Ferrini1, Patrick Brien1,6, Olaf
Bergmann7, Asmita Tingare1, Wolf Reik1, Ivar Sjaastad3, H. Llewelyn
Roderick1,6,* 1Epigenetics, Babraham Inst, Cambridge, UK. 2Lab of
Translational Genetics, VIB and KULeuven, Leuven, Belgium. 3IEMR,
University of Oslo and Oslo University Hospital, Oslo, Norway. 4Bjørknes
College, Oslo, Norway. 5University of Cambridge Metabolic Research Labs,
Addenbrooke's Hospital, Cambridge, UK. 6Dept of Cardiovascular Sciences
KULeuven, Leuven, Belgium. 7Cell and Molecular Biology, Karolinska Inst,
Stockholm, Sweden.
In response to increase workload, the heart elicits a hypertrophic response.
When induced by development, or as a result of exercise, the response is
adaptive, whereas when stimulated by disease conditions, the hypertrophic
response is maladaptive involving a re-expression of fetal genes, and is often
a precursor of future heart failure. Cardiac hypertrophy is mediated by
wholesale reprogramming of the myocyte transcriptome. Given that
methylation of lysines at position 9 and 27 in histone 3 (H3K9me2 and
H3K27me3) is a key determinant of transcriptional control mediating stable
gene silencing, we hypothesised that loss of these marks contributed to the
re-expression of fetal genes and the reprogramming of the myocyte
transcriptome during pathological hypertrophy. We performed a comparison of
the effect of hypertrophy induced by treadmill exercise (exercise; physiological
hypertrophy) and aortic banding (AB; pathological hypertrophy) upon the
genomic landscape of H3K9me2 and H3K27me3 (ChIP-Seq) in cardiac
myocytes. RNA levels in the same samples were determined by RNA-Seq. To
avoid confounding effects of fibrosis, DNA and RNA extracted from myocyte
nuclei isolated by flow cytometry. Gene expression patterns were distinct and
characteristic in myocytes isolated from AB and exercised rats. AB induced
fetal genes, whereas these were not induced in response to exercise. AB
induced a greater loss of H3K9me2 than exercise. In genomic regions where
H3K9me2 was lost, transcription of genes, including those of the fetal gene
programme, typical of the pathological hypertrophic response, were
increased. H3K27me3 did not change substantially in either model of
hypertrophy. Chemical or genetic (cardiac specific inducible KO) inhibition of
the enzymes responsible for alteration in H3K9me2 (Ehmt1/2) was sufficient
to induce a hypertrophic response, demonstrating the importance of this mark
in cardiac physiology. In conclusion, we have identified a new mechanism by
which the transcription underlying the hypertrophic response to pathological
stimuli is regulated.