Histone methyl-transferases and demethylases in the autophagy regulatory network: the emerging role of KDM1A/LSD1 demethylase

Abstract

Macroautophagy/autophagy is a physiological mechanism that is essential for the maintenance of cellular homeostasis and stress adaptation. Defective autophagy is associated with many human diseases, including cancer and neurodegenerative disorders. The emerging implication of epigenetic events in the control of the autophagic process opens new avenues of investigation and offers the opportunity to develop novel therapeutic strategies in diseases associated with dysfunctional autophagy-lysosomal pathways. Accumulating evidence reveals that several methyltransferases and demethylases are essential regulators of autophagy, and recent studies have led to the identification of the lysine demethylase KDM1A/LSD1 as a promising drug target. KDM1A/LSD1 modulates autophagy at multiple levels, participating in the transcriptional control of several downstream effectors. This review summarizes our current understanding of the role of KDM1A/LSD1 in the autophagy regulatory network.

Keywords: Autophagy; KDM1A/LSD1; chromatin; epigenetics; histone methylation.

Figure 1.

Methyltransferases linked to regulation of autophagy. (a) Starvation results in AMPK-dependent CARM1 protein stabilization and subsequent increases in histone H3R17 dimethylation and autophagy induction. (b) H3K27 trimethylation by EZH2 represses the expression of several MTOR pathway negative regulators, resulting in MTOR activation and the consequent inhibition of autophagy. (c) Under nutrient-rich conditions H3K9 dimethylation by EHMT2 suppress expression of genes essential for the autophagic process, maintaining autophagy at a low basal level. Induction of autophagy by starvation results in EHMT2 displacement, decreasing the H3K9me2 repressive mark and enhancing ATG gene expression. Dashed arrows indicate repression of gene expression.

Figure 2.

KDM1A coordinates the expression of several autophagy-related genes in neuroblastoma. KDM1A is recruited to the promoter region of SESN2 (by an unknown factor) and CLU (by MYCN) genes and represses their expression. KDM1A depletion triggers a structural remodeling in the chromatin landscape, leading to the accumulation of activating histone marks, transcriptional activation of CLU and SESN2 expression, and enhanced autophagy. Dashed arrows indicate repression of gene expression.

Figure 3.

KDM1A mediates hepatic post-prandial epigenetic repression of autophagy. In the fasting state, the CREBBP-CRTC2 complex, together with the histone acetyltransferase EP300, activates transcription of autophagy-related genes. In the early fed-state, NR1H4/FXR directly interacts with CREBBP and leads to the dissociation of EP300 and CRTC2, resulting in a reduction of activating histone marks and gene repression. In the late fed-state, NR0B2/SHP recruits KDM1A to a subset of CREBBP-bound autophagy genes. The presence of the KDM1A-NR0B2/SHP-CREBBP complex triggers an epigenetic repression state by accumulation of repressive histone marks, involving additional unknown epigenetic modifiers, sustaining postprandial repression of autophagy. Dashed arrows indicate repression of gene expression.