Local Genome Topology Can Exhibit an Incompletely Rewired 3D-Folding State during Somatic Cell Reprogramming.

Pluripotent genomes are folded in a topological hierarchy that reorganizes during differentiation. The extent to which chromatin architecture is reconfigured during somatic cell reprogramming is poorly understood. Here we integrate fine-resolution architecture maps with epigenetic marks and gene expression in embryonic stem cells (ESCs), neural progenitor cells (NPCs), and NPC-derived induced pluripotent stem cells (iPSCs). We find that most pluripotency genes reconnect to target enhancers during reprogramming. Unexpectedly, some NPC interactions around pluripotency genes persist in our iPSC clone. Pluripotency genes engaged in both "fully-reprogrammed" and "persistent-NPC" interactions exhibit over/undershooting of target expression levels in iPSCs. Additionally, we identify a subset of "poorly reprogrammed" interactions that do not reconnect in iPSCs and display only partially recovered, ESC-specific CTCF occupancy. 2i/LIF can abrogate persistent-NPC interactions, recover poorly reprogrammed interactions, reinstate CTCF occupancy, and restore expression levels. Our results demonstrate that iPSC genomes can exhibit imperfectly rewired 3D-folding linked to inaccurately reprogrammed gene expression.

The impact of social stress during adolescence or adulthood and coping strategy on cognitive function of female rats.

The age of stressor exposure can determine its neurobehavioral impact. For example, exposure of adolescent male rats to resident-intruder stress impairs cognitive flexibility in adulthood. The current study examined the impact of this stressor in female rats. Rats were exposed to resident-intruder stress during early adolescence (EA), mid-adolescence (MA) or adulthood (Adult). They were tested in an operant strategy-shifting task for side discrimination (SD), reversal learning (REV) and strategy set-shifting (SHIFT) the following week. Performance varied with age, stress and coping style. MA and EA rats performed SD and SHIFT better than other ages, respectively. Social stress impaired performance in rats depending on their coping strategy as determined by a short (SL) or long (LL) latency to become subordinate. SL rats were impaired in SD and REV, whereas EA-LL rats were impaired in SHIFT. These impairing effects of female adolescent stress did not endure into adulthood. Strategy set-shifting performance for female adolescents was positively correlated with medial prefrontal cortex (mPFC) activation as indicated by c-fos expression suggesting that this region is engaged during task performance. This contrasts with the inverse relationship between these indices reported for male adolescent rats. Together, the results demonstrate that social stress produces cognitive impairments for female rats that depend on age and coping style but unlike males, the impairing effects of female adolescent social stress are immediate and do not endure into adulthood. Sex differences in the impact of adolescent social stress on cognition may reflect differences in mPFC engagement during the task.