Repressive histone methylation regulates cardiac myocyte cell cycle exit

Abstract

Mammalian cardiac myocytes (CMs) stop proliferating soon after birth and subsequent heart growth comes from hypertrophy, limiting the adult heart's regenerative potential after injury. The molecular events that mediate CM cell cycle exit are poorly understood. To determine the epigenetic mechanisms limiting CM cycling in adult CMs (ACMs) and whether trimethylation of lysine 9 of histone H3 (H3K9me3), a histone modification associated with repressed chromatin, is required for the silencing of cell cycle genes, we developed a transgenic mouse model where H3K9me3 is specifically removed in CMs by overexpression of histone demethylase, KDM4D. Although H3K9me3 is found across the genome, its loss in CMs preferentially disrupts cell cycle gene silencing. KDM4D binds directly to cell cycle genes and reduces H3K9me3 levels at these promotors. Loss of H3K9me3 preferentially leads to increased cell cycle gene expression resulting in enhanced CM cycling. Heart mass was increased in KDM4D overexpressing mice by postnatal day 14 (P14) and continued to increase until 9-weeks of age. ACM number, but not size, was significantly increased in KDM4D expressing hearts, suggesting CM hyperplasia accounts for the increased heart mass. Inducing KDM4D after normal development specifically in ACMs resulted in increased cell cycle gene expression and cycling. We demonstrated that H3K9me3 is required for CM cell cycle exit and terminal differentiation in ACMs. Depletion of H3K9me3 in adult hearts prevents and reverses permanent cell cycle exit and allows hyperplastic growth in adult hearts in vivo.

High KDM1A Expression Associated with Decreased CD8+T Cells Reduces the Breast Cancer Survival Rate in Patients with Breast Cancer

“…Thus, research on the molecular mechanisms and signaling pathways involved in breast cancer metastasis and progression is important to improve survival. Furthermore, epigenetic regulation via methylation plays an important role that is closely related to the development and progression of breast cancer [ 5 , 6 , 7 ]. In addition, methylation status can provide critical information for advanced therapeutic trials in some patients [ 32 ].…”

“…Histone methylation primarily acts on lysine residues to regulate the suppression or activation of gene expression. Specific lysine methyltransferases (KMTs) and lysine demethylases (KDMs) reversibly regulate histone lysine methylation and are associated with several biological processes and diseases in humans [ 5 , 6 , 7 ].…”

High-Resolution 3D Fluorescent Imaging of Intact Tissues

“…Empowering immunolabeling and high resolution imaging techniques in thick tissues has special relevance to cardiology and studies of cardiac myocytes (CMs) which are >100 µm in size 23 . The inability to resolve small macromolecules, such as Aurora Kinase B localized to cytokinesis cleavage furrows or condensed chromatin labeled with mitosis marker phosphorylated histone H3, in whole CMs in situ has led to contentious views on the capacity of adult mammalian CMs to proliferate [24][25][26] .…”

“…Since epigenetic modifications on chromatin and nuclear morphology have been identified as key mediators of CM proliferation and cardiomyopathies 23,31-33 , we tested whether these features could be resolved by our technique. Nuclear morphology and subnuclear heterochromatin domains that stain positive for canonical heterochromatin markers Heterochromatin Protein 1 (HP1) and histone H3 Lysine 9 trimethylation (H3K9me3) 23 , were clearly resolved in 3D (Figure 3).…”

Knockdown of KDM1A suppresses tumour migration and invasion by epigenetically regulating the TIMP1/MMP9 pathway in papillary thyroid cancer

“…Histone lysine methylation is reversibly modulated by specific lysine methyltransferases (KMTs) and lysine demethylases (KDMs) and is involved in various biological processes and diseases in humans. [4][5][6][7] As the first demethylase discovered, KDM1A is the best characterized KDM. KDM1A is also known as LSD1 and AOF2, 8 and can interact with various protein complexes (eg CoREST, NuRD, RCOR2), receptors (eg oestrogen, androgen, TLX), non-histone proteins (eg p53, E2F1, DNMT1), and transcription factors (eg TLA and SNAIL).…”