SRP066235 PRJNA302265 GSE75032 MSL2 reads DNA shape to distinguish X from autosome for dosage compensation (MLE RNAi in S2 cells experiments) The rules according to which transcription factors selectively bind only a small subset of genomic sites from a vast pool of similar sequences are not understood. One of the most challenging tasks in DNA recognition is posed by dosage compensation systems that require the unequivocal distinction between a sex chromosome and all autosomes. In Drosophila melanogaster the male-specific-lethal dosage compensation complex (MSL-DCC) doubles the transcription output of most genes on the X chromosome via chromatin modification, but the nature of this selectivity is not known. We now found that MSL2, the male-specific organizer of the DCC, uses two distinct DNA interaction surfaces to read out previously identified X chromosomal ‘high affinity sites’. Specificity is provided by the interaction of the CXC domain with a novel, X-specific motif defined by DNA sequence and shape features. By several criteria these ‘PionX sites’ are primary determinants of X chromosome identity. Overall design: ChIP-Seq of MSL2 in S2 cells treated with control or MLE RNAi GSE75032 pubmed 27580037 parent_bioproject PRJNA302262