Cardiac hypertrophy and failure are accompanied by a reprogramming of gene expression that involves transcription factors and chromatin remodeling enzymes. Little is known about the roles of histone methylation and demethylation in this process. To understand the role of JMJD2A, a histone trimethyl demethylase, in cardiac hypertrophy, we generated mouse lines with heart-specific Jmjd2a deletion (hKO) and overexpression (Jmjd2a-Tg). Jmjd2a hKO and Jmjd2a-Tg mice had no overt baseline phenotype, but did demonstrate altered responses to cardiac stresses. While inactivation of Jmjd2a resulted in an attenuated hypertrophic response to transverse aortic constriction–induced (TAC-induced) pressure overload, Jmjd2a-Tg mice displayed exacerbated cardiac hypertrophy. We identified four-and-a-half LIM domains 1 (FHL1), a key component of the mechanotransducer machinery in the heart, as a direct target of JMJD2A. JMJD2A bound to the FHL1 promoter in response to TAC, upregulated FHL1 expression, and downregulated H3K9 trimethylation. Upregulation of FHL1 by JMJD2A was mediated through SRF and myocardin and required its demethylase activity. The expression of JMJD2A was upregulated in human hypertrophic cardiomyopathy patients. Our studies reveal that JMJD2A promotes cardiac hypertrophy under pathological conditions and suggest what we believe to be a novel mechanism for JMJD2A in reprogramming of gene expression involved in cardiac hypertrophy.

Background & Aims FoxO4 is a member of the forkhead box transcription factor O (FoxO) subfamily. FoxO proteins are involved in diverse biological processes. In this study, we examine the role of FoxO4 in intestinal mucosal immunity and inflammatory bowel disease (IBD). Methods Foxo4-null mice were subjected to trinitrobenzene sulfonic acid (TNBS) treatment. Microarray analysis and quantitative reverse transcription polymerase chain reaction were used to identify the cytokine transcripts that were altered by Foxo4 deletion. The effects of Foxo4 deficiency on the intestinal epithelial permeability and levels of tight junction proteins were examined by permeable fluorescent dye and Western blot. The molecular and cellular mechanisms by which FoxO4 regulates the mucosal immunity were explored through immunologic and biochemical analyses. The expression level of FoxO4 in intestinal epithelial cells of patients with IBD was examined with immunohistochemistry. Results Foxo4-null mice were more susceptible to TNBS injury–induced colitis. The chemokine CCL5 is significantly up-regulated in the colonic epithelial cells of Foxo4-null mice, with increased recruitment of CD4⁺ intraepithelial T cells and up-regulation of cytokines interferon-γ and tumor necrosis factor-α in the colon. Foxo4 deficiency also resulted in an increase in intestinal epithelial permeability and down-regulation of the tight junction proteins ZO-1 and claudin-1. Mechanistically, FoxO4 inhibited the transcriptional activity of nuclear factor-κB (NF-κB), and Foxo4 deficiency is associated with increased NF-κB activity in vivo. FoxO4 transcription is transiently repressed in response to TNBS treatment and in patients with IBD. Conclusion These results indicate that FoxO4 is an endogenous inhibitor of NF-κB and identify a novel function of FoxO4 in the regulation of NF-κB–mediated mucosal immunity.

Left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular morbidity and mortality. Pathological LVH engages transcriptional programs including reactivation of canonical fetal genes and those inducing fibrosis. Histone lysine demethylases (KDMs) are emerging regulators of transcriptional reprogramming in cancer, though their potential role in abnormal heart growth and fibrosis remains little understood. Here, we investigate gain and loss of function of an H3K9me2 specific demethylase, Kdm3a, and show it promotes LVH and fibrosis in response to pressure-overload. Cardiomyocyte KDM3A activates Timp1 transcription with pro-fibrotic activity. By contrast, a pan-KDM inhibitor, JIB-04, suppresses pressure overload-induced LVH and fibrosis. JIB-04 inhibits KDM3A and suppresses the transcription of fibrotic genes that overlap with genes downregulated in Kdm3a-KO mice versus WT controls. Our study provides genetic and biochemical evidence for a pro-hypertrophic function of KDM3A and proof-of principle for pharmacological targeting of KDMs as an effective strategy to counter LVH and pathological fibrosis.

Phenotypic modulation of vascular smooth muscle cells (SMCs) in the blood vessel wall from a differentiated to a proliferative state during vascular injury and inflammation plays an important role in restenosis and atherosclerosis. Matrix metalloproteinase 9 (MMP9) is a member of the MMP family of proteases, which participate in extracellular matrix degradation and turnover. MMP9 is upregulated and required for SMC migration during the development of restenotic and atherosclerotic lesions. In this study, we show that FoxO4 activates transcription of the MMP9 gene in response to tumor necrosis factor alpha (TNF-alpha) signaling. Inhibition of FoxO4 expression by small interfering RNA or gene knockout reduces the abilities of SMCs to migrate in vitro and inhibit neointimal formation and MMP9 expression in vivo. We further show that both the N-terminal, Sp1-interactive domain and the C-terminal transactivation domain of FoxO4 are required for FoxO4-activated MMP9 transcription. TNF-alpha signaling upregulates nuclear FoxO4. Our studies place FoxO4 in the center of a transcriptional regulatory network that links gene transcription required for SMC remodeling to upstream cytokine signals and implicate FoxO4 as a potential therapeutic target for combating proliferative arterial diseases.

Heart development comprises myocyte specification, differentiation and cardiac morphogenesis. These processes are regulated by a group of core cardiac transcription factors in a coordinated temporal and spatial manner. Histone methylation is an emerging epigenetic mechanism for regulating gene transcription. Interplay among cardiac transcription factors and histone lysine modifiers plays important role in heart development. Aberrant expression and mutation of the histone lysine modifiers during development and in adult life can cause either embryonic lethality or congenital heart diseases, and influences the response of adult hearts to pathological stresses. In this review, we describe current body of literature on the role of several common histone methylations and their modifying enzymes in heart development, congenital and adult heart diseases.