Wednesday 24
The specific sequence- and epigenetic state-dependent folding of chromosomes

› 11:30 - 12:00 (30min)
Topologically associating domain boundaries serve as hitchhiking platforms for the Drosophila dosage compensation complex
Fidel Ramirez  1@  , Thomas Lingg  2, 1  , Sarah Toscano  1  , Kin Chung Lam  1  , Plamen Georgiev  1  , Ho-Ryun Chung  3  , Bryan Lajoie  4  , Elzo De Wit  5  , Ye Zhan  4  , Wouter De Laat  5  , Job Dekker  4  , Thomas Manke  1  , Asifa Akhtar  1  
1 : The Max Planck Institute of Immunobiology and Epigenetics  (MPI-IE)  -  Website
Stübeweg 51 D-79108 Freiburg -  Germany
2 : Faculty of Biology,‭ ‬University of Freiburg  -  Website
3 : Max Planck Institute for Molecular Genetics  (MOLGEN)  -  Website
14195‭ ‬Berlin -  Germany
4 : Department of Biochemistry and Molecular Pharmacology,‭ ‬University of Massachusetts Medical School  (UMASS)  -  Website
Worcester,‭ ‬Massachusetts‭ ‬01605-0103, -  United States
5 : University Medical Center Utrecht  (UMC Utrecht)  -  Website
Uppsalalaan‭ ‬8,‭ ‬3584‭ ‬CT Utrecht -  Netherlands

Dosage compensation in flies,‭ ‬in contrast to mammals,‭ ‬increases gene expression from the single X chromosome in males.‭ ‬To achieve this the dosage compensation complex‭ (‬DCC‭) ‬in‭ ‬Drosophila melanogaster‭ ‬specifically recognizes the X chromosome and acetylates the histone H4‭ ‬of active genes.‭ ‬A set of genomic regions known as high-affinity sites‭ (‬HAS‭) ‬had been identified as the X-specific binding locations of the dosage compensation complex.‭ ‬However,‭ ‬HAS are scattered throughout the X chromosome but no logic behind such disposition is currently known.‭ ‬Using Hi-C data we demonstrate that HAS are non-randomly distributed,‭ ‬appearing almost exclusively at the boundaries of topologically associating domains‭ (‬TADs‭)‬.‭ ‬To understand the significance of this localization we analyzed Hi-C and‭ ‬4C-seq contact data and found that TAD boundaries display more contacts to each other as well a to other chromosomal regions as compared to any other genomic region.‭ ‬These features are sex-independent as Hi-C and‭ ‬4C-seq contact maps remain comparable between male,‭ ‬female and DCC knockdowns.‭ ‬Further experiments allowed us to differentiate a two step process in which dosage compensation progresses:‭ ‬First,‭ ‬the DCC‭ ‬targets the X chromosome by binding HAS at TAD boundaries,‭ ‬then the DCC‭ ‬spreads‭ ‬from HAS to reach spatially nearby genes.‭ ‬Thus,‭ ‬once the DCC is bound to the chromosome X,‭ ‬it spreads,‭ ‬probably by diffusion,‭ ‬to nearby chromatin.‭ ‬Based on our Hi-C and‭ ‬4C-seq data we argue that TAD boundaries offer the best location from which spatial spreading can reach most chromatin,‭ ‬this could explain why the high-affinity sites are almost exclusively found at boundaries.


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