Abstract
Intrinsically disordered regions (IDRs) are especially enriched among proteins that regulate chromatin and transcription. As a result, mechanisms that influence specificity of IDR-driven interactions have emerged as exciting unresolved issues for understanding gene regulation. We review the molecular elements frequently found within IDRs that confer regulatory specificity. In particular, we summarize the differing roles of disordered low-complexity regions (LCRs) and short linear motifs (SLiMs) towards selective nuclear regulation. Examination of IDR-driven interactions highlights SLiMs as organizers of selectivity, with widespread roles in gene regulation and integration of cellular signals. Analysis of recurrent interactions between SLiMs and folded domains suggests diverse avenues for SLiMs to influence phase-separated condensates and highlights opportunities to manipulate these interactions for control of biological activity.