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Emerging Evidence of Chromosome Folding by Loop Extrusion.

ABSTRACT: Chromosome organization poses a remarkable physical problem with many biological consequences: How can molecular interactions between proteins at the nanometer scale organize micron-long chromatinized DNA molecules, insulating or facilitating interactions between specific genomic elements? The mechanism of active loop extrusion holds great promise for explaining interphase and mitotic chromosome folding, yet remains difficult to assay directly. We discuss predictions from our polymer models of loop extrusion with barrier elements and review recent experimental studies that provide strong support for loop extrusion, focusing on perturbations to CTCF and cohesin assayed via Hi-C in interphase. Finally, we discuss a likely molecular mechanism of loop extrusion by structural maintenance of chromosomes complexes.

SUBMITTER: Fudenberg G

PROVIDER: S-EPMC6512960 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Emerging Evidence of Chromosome Folding by Loop Extrusion.

Fudenberg Geoffrey G Abdennur Nezar N Imakaev Maxim M Goloborodko Anton A Mirny Leonid A LA

Cold Spring Harbor symposia on quantitative biology 20170101

Chromosome organization poses a remarkable physical problem with many biological consequences: How can molecular interactions between proteins at the nanometer scale organize micron-long chromatinized DNA molecules, insulating or facilitating interactions between specific genomic elements? The mechanism of active loop extrusion holds great promise for explaining interphase and mitotic chromosome folding, yet remains difficult to assay directly. We discuss predictions from our polymer models of l ...[more]

PMID: 29728444

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Chromatin Fiber Folding Represses Transcription and Loop Extrusion in Quiescent Cells (ChIP-Seq)

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Project description:Two different models have been proposed to explain how the endpoints of chromatin looped domains ('TADs') in eukaryotic chromosomes are determined. In the first, a cohesin complex extrudes a loop until it encounters a boundary element roadblock, generating a stem-loop. In this model, boundaries are functionally autonomous: they have an intrinsic ability to halt the movement of incoming cohesin complexes that is independent of the properties of neighboring boundaries. In the second, loops are generated by boundary:boundary pairing. In this model, boundaries are functionally non-autonomous, and their ability to form a loop depends upon how well they match with their neighbors. Moreover, unlike the loop-extrusion model, pairing interactions can generate both stem-loops and circle-loops. We have used a combination of MicroC to analyze how TADs are organized, and experimental manipulations of the even skipped TAD boundary, homie, to test the predictions of the 'loop-extrusion' and the 'boundary-pairing' models. Our findings are incompatible with the loop-extrusion model, and instead suggest that the endpoints of TADs in flies are determined by a mechanism in which boundary elements physically pair with their partners, either head-to-head or head-to-tail, with varying degrees of specificity. Although our experiments do not address how partners find each other, the mechanism is unlikely to require loop extrusion.

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