Nuclear and Genome Organization in Development and Cancer

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Normal somatic cells have highly compartmentalized nuclear structure.

(see mapping the interphase nucleus image at right)

Neat RNA is an architectural RNA that scaffolds a large nuclear structure

Neat RNA is a non-coding RNA that is required for the formation of paraspeckles (see image below). Paraspeckles are ubiquitous nuclear structures (~10-30/nucleus) of unknown function found in all human primary and transformed cells.

Neat1-PSP1four-lineScangraph

Pluripotent stem cells have a unique nuclear organization lacking defined structural compartments.

The complex nuclear structure of somatic cells is a key component of epigenomic regulation, yet little is known about nuclear structure and genomic organization of pluripotent cells (e.g. hESC). Here we surveyed several nuclear structures in pluripotent and transitioning hESC. We find hESC have unique nuclear organization and lack numerous defined structural compartments seen in somatic cells. They also exhibit dramatically different PML-defined structures, which in somatic cells are linked to gene regulation and cancer.

SC35Differentiation

Human ES cells display epigenetic anomalies as revealed by X-inactivation.

X-inactivation has long been studied in mouse ES cells which recapitulate X-inactivation during differentiation. X-inactivation is a paradigm for one of the earliest steps in cell specialization through formation of facultative heterochromatin, and has not been studied in human ESC. We found that unlike in the mouse, hESC precociously inactivate one of the two X-chromosomes before differentiation and therefore are not a suitable model system to study this process in humans. We have therefore begun making human iPS lines and building an inducible transgene system in human ES cells (see last column).

Cancer nuclei show loss of distinct heterochromatic features.

Pathologists have long used gross changes in nuclear heterochromatin as markers of cancer cells. One of these heterochromatic changes seen in cancer is the loss of the Barr body of the inactive X-chromosome.

ChangesHeterochromatinFlow-chart

loss-peripheral-heterochromatinCancer cells loose the peripheral heterochromatic compartment.

Most normal somatic cells have a large region of silent heterochromatin located around the periphery of the nucleus and around the nucleolus. Many cancer cells appear to lose this compartment, suggesting inappropriate reactivation of silenced heterochromatin.

BRCA1 associates with heterochromatic centromeric satellite DNA during its replication.

Proper replication of centromeric DNA is essential to ensure appropriate segregation of chromosomes at mitosis. The link between BRCA1 and centromeric replication could connect BRCA1 to both epigenetic and genetic instability in cancers. We suggest that heterochromatic instability is a common but largely unexplored mechanism, leading to widespread genomic misregulation and the evolution of some cancers.

3D-image-composite BRCA