Synergistic interactions between MSL complex and the CLAMP protein regulate Drosophila dosage compensation. Marcela Soruco¹, Jessica Chery¹, Eric Bishop^2,7, Trevor Siggers³, Michael Tolstorukov^2,3, Alexander Leydon¹, Arthur Sugden¹, Karen Goebel¹, Jessica Feng¹, Peng Xia¹, Anastasia Vedenko³, Martha Bulyk^3,4,5, Peter Park^2,3,6, Erica Larschan¹. 1) Department of Molecular Biology, Cellular Biology and Biochemistry, Brown University, Providence, RI 02912; 2) Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115; 3) Division of Genetics, Department of Medicine, Brigham & Womens Hospital and Harvard Medical School, Boston, MA 02115; 4) Department of Pathology, Brigham & Womens Hospital and Harvard Medical School, Boston, MA, 02115; 5) Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115; 6) Childrens Hospital Informatics Program, Boston, MA 02115; 7) Bioinformatics Graduate Program, Boston University, Boston, MA 02215.

   In heterogametic species, the process of dosage compensation is required to equalize transcript levels between the sex chromosomes in males and females. The Drosophila Male-Specific Lethal (MSL) complex increases transcript levels on the single male X-chromosome to equal the transcript levels in XX females. However, the mechanism by which dosage compensation is targeted to the male X-chromosome is not understood because neither the MSL complex nor cis-acting DNA sequences are sufficient. Here, we demonstrate that a previously uncharacterized zinc-finger protein, CLAMP (Chromatin-Linked Adaptor for MSL Proteins), regulates X-chromosome specificity. CLAMP tethers MSL complex to the X-chromosome and exhibits a synergistic interaction with MSL complex that increases X-chromosome specificity. Also, CLAMP is highly enriched at likely "seed" sites prior to MSL complex recruitment. The discovery of CLAMP identifies a key factor that regulates the chromosome-specific targeting of dosage compensation and provides new insights into how sub- nuclear domains of coordinate gene regulation are formed within complex genomes.