Induction by left ventricular overload and left ventricular failure of the human Jumonji gene (JARID2) encoding a protein that regulates transcription and reexpression of a protective fetal program.
OBJECTIVE
We identified changes in Jumonji (JARID2) expression in failing human hearts and determined its effects on expressions of atrial natriuretic factor (ANF), myosin light chain 2a (MLC2A), and alpha myosin heavy chain (MHCA), genes associated with both human heart failure and the fetal gene program.


METHODS
Left ventricular outflow tract cardiac biopsy samples were taken from 31 patients with aortic valvular stenosis. Hearts were grouped according to left ventricular size and function: nonfailing hearts (undilated with good function) and failing hearts (dilated with poor function). Protein levels were determined by Western blotting, and messenger RNA transcript levels by ratiometric reverse transcriptase-polymerase chain reaction. Luciferase assays in HL-2 cells were used to assess effects of Jarid2 on Anf, Mlc2a, and Mhca transcriptions. Chromatin immunoprecipitation was used to detect interaction of JARID2 with specific target-gene promoters.


RESULTS
JARID2 and MHCA expressions were reduced in failing hearts, whereas MLC2A and ANF were increased. In HL-2 cell culture, Jarid2 suppressed Anf and Mlc2a but enhanced Mhca. Jarid2 expression was reduced by cyclic mechanical stress, with concomitant increased Anf and Mlc2a and decreased Mhca expressions, reproducing the expression profile found in decompensated human pressure overload.


CONCLUSIONS
Jumonji expression is reduced by mechanical stress in human heart failure from aortic stenosis. JARID2 regulates ANF, MLC2A, and MHCA transcription and contributes to reexpression of the fetal gene program in decompensated aortic stenosis. JARID2 appears important in transcriptional regulation of fetal genes and may emerge as a diagnostic marker for left ventricular decompensation in aortic stenosis.
Bovill
Esta
E
Department of Medicine, University College London, London, UK. ebovill@doctors.net.uk
Westaby
Stephen
S
Reji
Shiney
S
Sayeed
Rana
R
Crisp
Alastair
A
Shaw
Tony
T
D000818:Animals; D001024:Aortic Valve Stenosis / Q000150:complications; D009320:Atrial Natriuretic Factor / Q000032:analysis*; D015153:Blotting, Western; D024722:Cardiac Myosins / Q000032:analysis*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics*; D006801:Humans; D051379:Mice; D008875:Middle Aged; D018994:Myosin Light Chains / Q000032:analysis*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D063151:Polycomb Repressive Complex 2; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013314:Stress, Mechanical; D014157:Transcription Factors / Q000032:analysis; D014158:Transcription, Genetic / Q000502:physiology*; D024723:Ventricular Myosins / Q000032:analysis*
C093650:Jarid2 protein, mouse; D018994:Myosin Light Chains; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C107184:myosin light chain 2; D009320:Atrial Natriuretic Factor; D063151:Polycomb Repressive Complex 2; D024722:Cardiac Myosins; D024723:Ventricular Myosins