Lysine-specific histone demethylase 1A–CoREST complex (LSD1–CoREST complex)

The Lysine-specific histone demethylase 1A–CoREST complex (LSD1–CoREST complex) is a multi-protein epigenetic regulator comprising the enzyme LSD1 (KDM1A), the corepressor protein CoREST (REST corepressor 1, RCOR1), and often additional components such as HDAC1/2. LSD1 functions as a flavin adenine dinucleotide (FAD)-dependent histone demethylase, specifically removing methyl groups from mono- and dimethylated lysine 4 on histone H3 (H3K4me1/2)—a mark associated with active gene transcription. CoREST is essential for enabling LSD1 to demethylate nucleosomal histones rather than just free histone peptides, as it mediates binding to both DNA and histones within the nucleosome[2][5][6]. The complex is critical for transcriptional repression, cell differentiation, and maintenance of cellular identity. Structural studies show a flexible, bi-lobed architecture, accommodating the activities of both LSD1 and associated histone deacetylases (HDAC1/2) within the same complex, providing coupled demethylase and deacetylase activities for chromatin remodeling[1][5][6]. Dysregulation and overexpression of the LSD1–CoREST complex have been implicated in various cancers and are being actively targeted by small-molecule inhibitors currently in clinical development[3][6].

Other names

KDM1A–CoREST complexLSD1/CoRESTLSD1:RCOR1 complexKDM1A–RCOR1 complex

LSD1 inhibition blocks demethylation of H3K4, leading to reactivation of silenced genes including differentiation and tumor suppressor genes[6][3]. Disruption of the LSD1–CoREST complex impairs its chromatin binding and epigenetic repression functions[2][3]. Dual inhibition within the complex (e.g., targeting both LSD1 and HDAC1) may affect both methylation and acetylation status[1][6].