Static And Dynamic DNA Loops Form AP-1 Bound Activation Hubs During Macrophage Development

Phanstiel, D. H.; Van Bortle, K.; Spacek, D. V.; Hess, G. T.; Saad Shamim, M.; Machol, I.; Love, M. I.; Lieberman Aiden, E.; Bassik, M. C.; Snyder, M. P.

doi:10.1101/142026

bioRxiv · 10.1101/142026

Static And Dynamic DNA Loops Form AP-1 Bound Activation Hubs During Macrophage Development

Phanstiel, D. H.·Van Bortle, K.·Spacek, D. V.·Hess, G. T.·Saad Shamim, M.·Machol, I.·Love, M. I.·Lieberman Aiden, E.·Bassik, M. C.·Snyder, M. P.

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Abstract

The three-dimensional arrangement of the human genome comprises a complex network of structural and regulatory chromatin loops important for coordinating changes in transcription during human development. To better understand the mechanisms underlying context-specific 3D chromatin structure and transcription during cellular differentiation, we generated comprehensive in situ Hi-C maps of DNA loops during human monocyte-to-macrophage differentiation. We demonstrate that dynamic looping events are regulatory rather than structural in nature and uncover widespread coordination of dynamic enhancer activity at preformed and acquired DNA loops. Enhancer-bound loop formation and enhancer-activation of preformed loops represent two distinct modes of regulation that together form multi-loop activation hubs at key macrophage genes. Activation hubs connect 3.4 enhancers per promoter and exhibit a strong enrichment for Activator Protein 1 (AP-1) binding events, suggesting multi-loop activation hubs driven by cell-type specific transcription factors may represent an important class of regulatory chromatin structures for the spatiotemporal control of transcription.\n\nHIGHLIGHTSO_LIHigh resolution and high sensitivity of loop detection via deeply sequenced in situ Hi-C experiments during monocyte to macrophage differentiation (> 10 billion total reads)\nC_LIO_LIMulti-loop interaction communities identified surrounding key macrophage genes.\nC_LIO_LIMulti-loop communities connect dynamic enhancers through both static and newly acquired DNA loops, forming hubs of activation\nC_LIO_LIMacrophage activation hubs are enriched for AP-1 bound long-range enhancer interactions, suggesting cell-type specific TFs drive changes in 3D structure and transcription through regulatory DNA loops\nC_LI

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Phanstiel, D. H., Van Bortle, K., Spacek, D. V., Hess, G. T., Saad Shamim, M., Machol, I., Love, M. I., Lieberman Aiden, E., Bassik, M. C., Snyder, M. P.. 2017-05-25. Static And Dynamic DNA Loops Form AP-1 Bound Activation Hubs During Macrophage Development. https://doi.org/10.1101/142026

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