KDM1A

KDM1A, also known as lysine-specific demethylase 1A or LSD1, is a flavin adenine dinucleotide (FAD)-dependent histone demethylase that modulates chromatin and gene expression. The enzyme primarily removes methyl groups from mono- and di-methylated lysine 4 on histone H3 (H3K4me1/2), a mark associated with active transcription, and in certain contexts can also demethylate H3K9me1/2 when part of specific transcriptional complexes. LSD1 activity is directed by protein partners, most notably the CoREST corepressor complex, which includes REST and HDACs, guiding repression of target genes.

Structurally, LSD1 contains an amine oxidase catalytic domain that binds FAD and interacts with auxiliary domains to facilitate substrate recognition and protein interactions. As part of the CoREST complex, LSD1 coordinates chromatin modification with other epigenetic enzymes, linking histone demethylation to broader regulatory programs.

Biological roles of KDM1A are diverse and include regulation of development, neural differentiation, hematopoiesis, and stem cell maintenance. Through control of gene expression programs, LSD1 influences cell fate decisions and responses to developmental cues. Dysregulation of KDM1A expression or LSD1 activity has been implicated in several cancers, where its activity supports tumor cell proliferation, survival, and the maintenance of cancer stem cells. This has spurred interest in developing LSD1 inhibitors as therapeutic agents, evaluated in preclinical studies and clinical trials, often in combination with differentiation-inducing strategies or other epigenetic drugs.

KDM1A was identified in 2004 by Shi and colleagues as the first histone demethylase, establishing a new class of chromatin-modifying enzymes. The gene is the encodings for LSD1.