Conservation and diversity of the eukaryotic SAGA coactivator complex across kingdoms

Abstract

The SAGA complex is an evolutionarily conserved transcriptional coactivator that regulates gene expression through its histone acetyltransferase and deubiquitylase activities, recognition of specific histone modifications, and interactions with transcription factors. Multiple lines of evidence indicate the existence of distinct variants of SAGA among organisms as well as within a species, permitting diverse functions to dynamically regulate cellular pathways. Our co-expression analysis of genes encoding human SAGA components showed enrichment in reproductive organs, brain tissues and the skeletal muscle, which corresponds to their established roles in developmental programs, emerging roles in neurodegenerative diseases, and understudied functions in specific cell types. SAGA subunits modulate growth, development and response to various stresses from yeast to plants and metazoans. In metazoans, SAGA further participates in the regulation of differentiation and maturation of both innate and adaptive immune cells, and is associated with initiation and progression of diseases including a broad range of cancers. The evolutionary conservation of SAGA highlights its indispensable role in eukaryotic life, thus deciphering the mechanisms of action of SAGA is key to understanding fundamental biological processes throughout evolution. To illuminate the diversity and conservation of this essential complex, here we discuss variations in composition, essentiality and co-expression of component genes, and its prominent functions across Fungi, Plantae and Animalia kingdoms.

Keywords: Cancer; Coactivator; Development; Disease; Epigenetics; Evolution; GCN5; SAGA complex; Stress; Transcription.

Fig. 1

Schematic illustration of SAGA composition variations and function across kingdoms. Orthologues of yeast Spt8 is not found in higher eukaryotic SAGA complexes. Corresponding components of yeast Chd1/Arabidopsis CHR5 are not present in metazoans. Arabidopsis lack orthologues of yeast Sgf73/metazoan ATXN7. SF3B3 and SF3B5 components of the splicing module are not observed in yeast and not confirmed in Arabidopsis. PCAF can replace GCN5 specifically in vertebrates. In all eukaryotes, SAGA catalyzes acetylation (Ac) and removal of ubiquitylation (Ub) on histone tails and interacts with transcription factors (TFs), activating transcription of target genes to further regulate biological outcomes in development, stress response, immunity and disease. SAGA can also acetylate and deubiquitylate TFs to affect their stability and activity

Fig. 2

Expression pattern of human SAGA components in organs, tissues and blood cells. Normalized expression (NX) levels were obtained from the consensus dataset on the Human Protein Atlas database. Clustering of expression was generated using the heatmap package in R program. Expression levels are overall high to low from left to right and top to bottom in each module segment. Gray boxes indicate unavailable values. ATXN7-205–210 and ATXN7-212–214 represent two expression profiles of ATXN7 variants