The Integrator complex at the crossroad of coding and noncoding RNA

Abstract

Genomic transcription is fundamental to all organisms. In metazoans, the Integrator complex is required for endonucleolytic processing of noncoding RNAs, regulation of RNA polymerase II pause-release, and premature transcription attenuation at coding genes. Recent insights into the structural composition and evolution of Integrator subunits have informed our understanding of its biochemical functionality. Moreover, studies in multiple model organisms point to an essential function of Integrator in signaling response and cellular development, highlighting a key role in neuronal differentiation. Indeed, alterations in Integrator complex subunits have been identified in patients with neurodevelopmental diseases and cancer. Taken together, we propose that Integrator is a central regulator of transcriptional processes and that its evolution reflects genomic complexity in regulatory elements and chromatin architecture.

Keywords: Cancer; INTS evolution; Integrator complex; Neurodevelopmental diseases; RNA processing; Transcription regulation.

Figure 1.. Evolution of the Integrator complex.

a) Overview of the INTS gene ages throughout evolution. Eukarya (nucleated cells), Opisthokonta (uniflagellate cells), Eumetazoa (animals, except sponges), Bilateria (animals with bilateral body symmetry and three germ layers). b) Heatmap of the presence/absence of Integrator-homologous proteins in >300 species (compared to full-length human sequences with the following cut-offs: 30% pair-wise sequence identity, and 50% coverage of the human proteins, in addition to blastp default parameters [29]). Grayscale accounts for the number of hits in one species that aligned to a human INTS. c) Phylogenetic tree of the metallo-β-lactamase superfamily from eggNOG 4.5.1 (COG1236) [33]. Triangle length indicates divergence and triangle height the number of species. Below: domain architecture of human INTS9, CPSF2, INTS11, and CPSF3, as retrieved from Pfam 33.1 [32]. In red CPSF73–100_C domain. d) Model of INTS and their modular interactions. Cleavage module depicted in pink, stem-loop binding module in yellow, and reader module in cyan. Bold: catalytic subunit INTS11.

Figure 2.. Integrator’s main functions on coding genes in human and Drosophila.

a) The travelling matrix separates positional RNAPII changes at promoters and gene bodies into four classes. Graphical depiction of ~3100 significant Integrator-responsive genes [19]. In human, INTS11 depletion predominantly leads to downregulation of actively engaged RNAPII (class III and IV: 67%). Class IV genes are additionally characterized by increased RNAPII pause (33%). b and c) Model representation of Integrator’s functions in human and Drosophila. b) The Integrator complex cleaves promoter-associated small transcripts to allow paused RNAPII eviction and transcriptional elongation by productive RNAPII (class IV). c) Integrator is required for the premature termination (attenuation) of RNAPII transcription.