Heterochromatin drives organization of conventional and inverted nuclei

Martin Falk, Yana Feodorova, Natasha Naumova, Maxim Imakaev, Bryan R. Lajoie, Heinrich Leonhardt, Boris Joffe, Job Dekker, Geoffrey Fudenberg, Irina Solovei, Leonid Mirny

Preprint posted on January 09, 2018

How is chromatin organized in 3D inside the nucleus? A new preprint uses Hi-C and microscopy to show the leading role of heterochromatin-driven phase separation and anchoring to the nuclear lamina in this process

Selected by Boyan Bonev

Why is it important?

3D chromatin organization is a key mechanism to regulate gene expression and cell fate. At the megabase scale, the genome is segmented into distinct topological units called domains or TADs; recent work has provided many lines of evidence that a cohesin-based mechanism of loop extrusion is essential for this level of organization. However, how distant regions with similar epigenetic nature interact in the 3D space of the nucleus to form higher-order structures called compartments is still unclear.

What are the key findings? 

In this preprint Mirny and colleagues explore the 3D nuclear architecture of rod photoreceptors, which are characterized by a peculiar inverted architecture with heterochromatin located in the nuclear core and euchromatin in the periphery. With a combination of microscopy and Hi-C based approaches they determined that the segregation into active/inactive compartments appears surprisingly unaffected in rod photoreceptors, despite the inversion evident by microscopy (Figure 1). Using polymer modeling and timecourse experiments they were able to show that compartmentalization in the nucleus is driven primarily by heterochromatin regions and surprisingly does not depend on interactions with the lamina or contacts between euchromatin regions. These results indicate that the inverted morphology of rod photoreceptor cells represents the default state of chromatin organization and additional mechanisms, such as the lamina anchoring of heterochromatin, are necessary to obtain the 3D nuclear architecture evident in most eukaryotic cells.

Figure 1. Rod neurons display inverted nuclear architecture by microscopy (A), but normal compartmentalization by Hi-C (B)   (Falk et al., bioRxiv 2018)

Questions arising

  1. Why do most cells have conventional topology (periphery-anchored heterochromatin) if it is dispensable for compartmentalization?
  2. Is heterochromatin aggregation driven by phase separation?
  3. How is compartmentalization affected in other cells with unconventional nuclear morphology (like plasma cells)?

Related Research

Solovei, I., et. al. & Joffe, B. LBR and lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation. Cell 152, 584–598 (2013).
Solovei, I. et al. Nuclear architecture of rod photoreceptor cells adapts to vision in mammalian evolution. Cell 137, 356–368 (2009).
Dekker, J. & Mirny, L. Perspective. Cell 164, 1110–1121 (2016).

Tags: 3d genome, chromatin, epigenetics, neurons, nuclear architecture

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