The non‐specific lethal ( NSL ) complex at the crossroads of transcriptional control and cellular homeostasis

Abstract

The functionality of chromatin is tightly regulated by post‐translational modifications that modulate transcriptional output from target loci. Among the post‐translational modifications of chromatin, reversible ε‐lysine acetylation of histone proteins is prominent at transcriptionally active genes. Lysine acetylation is catalyzed by lysine acetyltransferases (KATs), which utilize the central cellular metabolite acetyl‐CoA as their substrate. Among the KATs that mediate lysine acetylation, males absent on the first (MOF/KAT8) is particularly notable for its ability to acetylate histone 4 lysine 16 (H4K16ac), a modification that decompacts chromatin structure. MOF and its non‐specific lethal (NSL) complex members have been shown to localize to gene promoters and enhancers in the nucleus, as well as to microtubules and mitochondria to regulate key cellular processes. Highlighting their importance, mutations or deregulation of NSL complex members has been reported in both human neurodevelopmental disorders and cancer. Based on insight gained from studies in human, mouse, and Drosophila model systems, this review discusses the role of NSL‐mediated lysine acetylation in a myriad of cellular functions in both health and disease. Through these studies, the importance of the NSL complex in regulating core transcriptional and signaling networks required for normal development and cellular homeostasis is beginning to emerge.

Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability

“…The severe impact of p.Tyr90Cys, p.Arg98Gln, and p.Arg99Gln on H4K16 acetylation (bottom 2 panels, lanes [5][6][7][8] suggests that the chromobarrel domain is essential for KAT8 to acetylate nucleosomal H4K16. To substantiate this, we analyzed KAT8 is the catalytic subunit of 2 multiprotein complexes important for genome-wide epigenetic regulation (Supplemental Figure 10B) (48,49), raising the intriguing question of how they contribute to the critical role of KAT8 in regulating cerebral development ( Figure 8E). Subunits of the complexes are well expressed in the cerebral cortex of neonatal mice and neurospheres cultured from mouse embryos (Supplemental Figure 1, B and C) this, inducible Kat8 deletion triggers apoptosis in myeloid cells (47).…”

Moonlighting in Mitosis: Analysis of the Mitotic Functions of Transcription and Splicing Factors

“…The nonspecific lethal (NSL) complex is a highly conserved multiprotein assembly that regulates gene transcription in both Drosophila and mammals. The human NSL complex, also called KAT8-associated nonspecific lethal (KANSL), comprises 8 proteins (KANSL1, KANSL2, KANSL3, MCRS1, PHF20, WDR5, HCF1/HCFC1, and OGT) that associate with the MOF/KAT8 acetyltransferase to regulate transcription of a specific set of genes and contribute to stem cell identity [115][116][117]. The Drosophila NSL complex contains at least six evolutionarily conserved Mof-associated proteins, namely, Nsl1 (KANSL1), Dgt1 (KANSL2), Rcd1 (KANSL3), Rcd5 (MCRS1), MBD-R2 (PHF20), and Wds (WDR5).…”

Evolutionary conserved NSL complex/BRD4 axis controls transcription activation via histone acetylation

“…The Koolen-de Vries syndrome is a complex neurodevelopmental disorder caused by haploinsufficiency of KANSL1 6,7 . Given the high level of evolutionary conservation in NSL complex targets between flies and mammals 14 , we hypothesized that the BRD4-related gene expression signature would also be evident in affected individuals. To address this question, we cultured primary fibroblast cell lines from Koolen-de Vries patients and healthy controls and performed RNA-seq experiments.…”

“…The spectrum of the NSL target genes encompasses diverse cellular functions from cell cycle to metabolism [11][12][13][14] . Tethering of the NSL complex to a reporter gene triggers strong transcription activation 15 .…”