Akirin proteins in development and disease: critical roles and mechanisms of action

Abstract

The Akirin genes, which encode small, nuclear proteins, were first characterized in 2008 in Drosophila and rodents. Early studies demonstrated important roles in immune responses and tumorigenesis, which subsequent work found to be highly conserved. More recently, a multiplicity of Akirin functions, and the associated molecular mechanisms involved, have been uncovered. Here, we comprehensively review what is known about invertebrate Akirin and its two vertebrate homologues Akirin1 and Akirin2, highlighting their role in regulating gene expression changes across a number of biological systems. We detail essential roles for Akirin family proteins in the development of the brain, limb, and muscle, in meiosis, and in tumorigenesis, emphasizing associated signaling pathways. We describe data supporting the hypothesis that Akirins act as a "bridge" between a variety of transcription factors and major chromatin remodeling complexes, and discuss several important questions remaining to be addressed. In little more than a decade, Akirin proteins have gone from being completely unknown to being increasingly recognized as evolutionarily conserved mediators of gene expression programs essential for the formation and function of animals.Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. https://www.springer.com/aamterms-v1

Function of cofactor Akirin2 in the regulation of gene expression in model human Caucasian neutrophil-like HL60 cells

“…Previous results support that Akirin2-IPs interactions regulate chromatin remodeling through ring finger protein 123 (RNF123) interaction with histone H3.1 [46] and ACL6A [43]. Akirin colocalizes with histone H3.1 and Brahma chromatin remodeling complex and was detected at an actively transcribed gene locus [17].…”

“…Of them, smarce1 (coding for SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1), satb1 and satb2 (coding for DNA-binding proteins SATB) were differentially regulated in response to akirin2 KO (Supplementary Data S5). The gene coding for the actin-like protein 6 (ACL6A) that has been implicated in interactions with Akirin2 and chromatin remodeling [43] was identified as up-regulated in response to akirin2 KO in HL60 cells (Supplementary Data S5). Additionally, a gene identified with 0.91% relative importance in the network analysis after akirin2 KO, and thus likely regulated by Akirin2, was KLF2 coding for Krueppel-like factor 2, which is involved in epigenetic regulation of gene expression [44,45] (Supplementary Data S4).…”

p53-mediated neurodegeneration in the absence of the nuclear protein Akirin2

“…Aki2 regulates gene expression patterns in many organisms in a cell type- and context-dependent manner (Komiya et al, 2008; Nowak et al, 2012; Akiyama et al, 2013; Bonnay et al, 2014; Komiya et al, 2014; Tartey et al, 2014; Bosch et al, 2020). We thus hypothesized that Aki2 regulates overlapping, but distinct, gene patterns throughout the generation and maturation of the cortical neuronal lineage.…”

“…The small, nuclear protein, Aki2, is broadly expressed in an array of tissues where its most consistently reported functions include the control of cell proliferation and differentiation (Bosch et al, 2020). The expression of Aki2 in non-proliferating cells such as maturing postnatal neurons suggested additional roles.…”

“…Proper regulation of gene expression patterns is critical for preventing such aberrant cell cycle re-entry and thus for postmitotic neuron maintenance and survival. Akirin2 (Aki2) is a highly-conserved, nuclear protein that regulates gene expression by interacting with transcription factors (Nowak et al, 2012;Bonnay et al, 2014;Tartey et al, 2014) and members of chromatin remodeling complexes (Giot et al, 2003;Nowak et al, 2012;Bonnay et al, 2014;Tartey et al, 2014;Tartey et al, 2015;Liu et al, 2017); reviewed by (Bosch et al, 2020). Invertebrates such as C. elegans and Drosophila harbor a single Akirin gene in their genomes, whilst mammals have two homologues (Akirin1 and Akirin2).…”