Discrete histone marks are translated into degenerate readouts by reader proteins (739.11)

The current paradigm to evaluate the combinatorial regulatory effect of histone modifications on gene transcription is to consider individual histone sites as the primary/basic functional units which are distinct from one another. However, numerous observations in chromatin biology cannot be explained by this paradigm. We propose a new framework to reconcile the evidences conflicting with the current paradigm: the individual histone sites can be functionally degenerate; thus, when considering combinatorial histone modifications, combination of these degenerate modifications but not that of the individual sites should be considered. This framework is based on our observation of significant degenerate binding between chromodomains and histone peptides, i.e. different histone sites can be recognized by the same set of chromodomains, and different chromodomains can share similar binding profiles to individual histone sites. Such degenerate binding is not dictated by amino acid sequence or PTM motif but rather rooted in the physiochemical properties defined by the PTMs on the histone peptides. This molecular mechanism is confirmed by the accurate prediction of the binding specificity by a computational model that captures the structural and energetic patterns of the domain‐peptide interaction. Our work represents the first but a crucial step towards elucidating the fundamental mechanism by which histone modifications correlate with their biological outputs. Grant Funding Source : NIH