A Specific LSD1/KDM1A Isoform Regulates Neuronal Differentiation through H3K9 Demethylation

Abstract

Lysine-specific demethylase 1 (LSD1) has been reported to repress and activate transcription by mediating histone H3K4me1/2 and H3K9me1/2 demethylation, respectively. The molecular mechanism that underlies this dual substrate specificity has remained unknown. Here we report that an isoform of LSD1, LSD1+8a, does not have the intrinsic capability to demethylate H3K4me2. Instead, LSD1+8a mediates H3K9me2 demethylation in collaboration with supervillin (SVIL), a new LSD1+8a interacting protein. LSD1+8a knockdown increases H3K9me2, but not H3K4me2, levels at its target promoters and compromises neuronal differentiation. Importantly, SVIL co-localizes to LSD1+8a-bound promoters, and its knockdown mimics the impact of LSD1+8a loss, supporting SVIL as a cofactor for LSD1+8a in neuronal cells. These findings provide insight into mechanisms by which LSD1 mediates H3K9me demethylation and highlight alternative splicing as a means by which LSD1 acquires selective substrate specificities (H3K9 versus H3K4) to differentially control specific gene expression programs in neurons.

Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation

“…It is also possible that inhibitory molecules bind to the exon 2a sequence, thereby reducing the activity of the isoform (1/2). This hypothesis is partly substantiated by a recent report of Laurent et al, 41 in which the full-length isoform of LSD1 fails to show demethylating activity against both H3K4 and H3K9 in vitro, but it effectively demethylates H3K9 but not H3K4 in neuronal cells. They identified the SVIL protein as an auxiliary molecule for LSD1 (1/1) to mediate specific H3K9 demethylation and subsequent transactivation of target genes in vivo.…”

Local chromatin microenvironment determines DNMT activity: from DNA methyltransferase to DNA demethylase or DNA dehydroxymethylase

“…Currently, there are 2 known classes of histone demethylases: the Flavin-dependent histone demethylases and the Jumonji-containing histone demethylases. The first class, containing lysine-specific histone demethylase 1 and 2 (LSD1, 2), is involved in modulating gene expression through demethylation of either mono-or di-methyllysine residues of H3K4 [38][39][40][41] or H3K9 [42][43][44] resulting in gene repression or gene activation, respectively. 45 During this histone demethylation process, H 2 O 2 is produced, 46 which has been proposed to be involved in signaling processes.…”

G-quadruplex RNA binding and recognition by the lysine-specific histone demethylase-1 enzyme

“…A primary function of LSD1 is to influence gene expression and chromatin structure by catalyzing the removal of mono-and dimethyl functional groups from Histone 3 proteins at lysine positions 4 and 9 (H3K4/K9) (Shi et al 2004;Forneris et al 2007;Laurent et al 2015). LSD1 interacts with over 60 gene regulatory proteins, including transcription factors (CoREST, REST, p53, E2F1) and key enzymes (DNMT1, MRE11, HDAC1/2), as well as essential nutrients (tetrahydrofolate [THF]) (Luka et al 2011;Kooistra and Helin 2012;Chatr-Aryamontri et al 2013).…”