The three-dimensional folding of the α-globin gene domain reveals formation of chromatin globules
Department of Cell Biology; Program in Gene Function and Expression; Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
Chromatin; Chromosomes, Human, Pair 16; Humans; In Situ Hybridization, Fluorescence; K562 Cells; Models, Molecular; Nucleic Acid Conformation; alpha-Globins
Biochemistry, Biophysics, and Structural Biology | Cell Biology | Genetics and Genomics
We developed a general approach that combines chromosome conformation capture carbon copy (5C) with the Integrated Modeling Platform (IMP) to generate high-resolution three-dimensional models of chromatin at the megabase scale. We applied this approach to the ENm008 domain on human chromosome 16, containing the α-globin locus, which is expressed in K562 cells and silenced in lymphoblastoid cells (GM12878). The models accurately reproduce the known looping interactions between the α-globin genes and their distal regulatory elements. Further, we find using our approach that the domain folds into a single globular conformation in GM12878 cells, whereas two globules are formed in K562 cells. The central cores of these globules are enriched for transcribed genes, whereas nontranscribed chromatin is more peripheral. We propose that globule formation represents a higher-order folding state related to clustering of transcribed genes around shared transcription machineries, as previously observed by microscopy.
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Citation: Nature Structural & Molecular Biology. 2011 Jan;18(1):107-14. Epub 2010 Dec 5. doi:10.1038/nsmb.1936. Link to article on publisher's site