Global Genome Conformational Programming during Neuronal Development Is Associated with CTCF and Nuclear FGFR1-The Genome Archipelago Model.

During the development of mouse embryonic stem cells (ESC) to neuronal committed cells (NCC), coordinated changes in the expression of 2851 genes take place, mediated by the nuclear form of FGFR1. In this paper, widespread differences are demonstrated in the ESC and NCC inter- and intra-chromosomal interactions, chromatin looping, the formation of CTCF- and nFGFR1-linked Topologically Associating Domains (TADs) on a genome-wide scale and in exemplary HoxA-D loci. The analysis centered on HoxA cluster shows that blocking FGFR1 disrupts the loop formation. FGFR1 binding and genome locales are predictive of the genome interactions; likewise, chromatin interactions along with nFGFR1 binding are predictive of the genome function and correlate with genome regulatory attributes and gene expression. This study advances a topologically integrated genome archipelago model that undergoes structural transformations through the formation of nFGFR1-associated TADs. The makeover of the TAD islands serves to recruit distinct ontogenic programs during the development of the ESC to NCC.

Induced Pluripotent Stem Cells Reveal Common Neurodevelopmental Genome Deprograming in Schizophrenia.

Schizophrenia is a neurodevelopmental disorder characterized by complex aberrations in the structure, wiring, and chemistry of multiple neuronal systems. The abnormal developmental trajectory of the brain is established during gestation, long before clinical manifestation of the disease. Over 200 genes and even greater numbers of single nucleotide polymorphisms and copy number variations have been linked with schizophrenia. How does altered function of such a variety of genes lead to schizophrenia? We propose that the protein products of these altered genes converge on a common neurodevelopmental pathway responsible for the development of brain neural circuit and neurotransmitter systems. The results of a multichanneled investigation using induced pluripotent stem cell (iPSCs)- and embryonic stem cell (ESCs)-derived neuronal committed cells (NCCs) indicate an early (preneuronal) developmental-genomic etiology of schizophrenia and that the dysregulated developmental gene networks are common to genetically unrelated cases of schizophrenia. The results support a "watershed" mechanism in which mutations within diverse signaling pathways affect the common pan-ontogenic mechanism, integrative nuclear (n)FGFR1 signaling (INFS). Dysregulation of INFS in schizophrenia NCCs deconstructs coordinated gene networks and leads to formation of new networks by the dysregulated genes. This genome deprograming affects critical gene programs and pathways for neural development and functions. Studies show that the genomic deprograming reflect an altered nFGFR1-genome interactions and deregulation of miRNA genes by nFGFR1. In addition, changes in chromatin topology imposed by nFGFR1 may play a role in coordinate gene dysregulation in schizophrenia.

Prolonged noise exposure-induced auditory threshold shifts in rats.

Noise-induced hearing loss (NIHL) initially increases with exposure duration, but eventually reaches an asymptotic threshold shift (ATS) once the exposure duration exceeds 18-24 h. Equations for predicting the ATS have been developed for several species, but not for rats, even though this species is extensively used in noise exposure research. To fill this void, we exposed rats to narrowband noise (NBN, 16-20 kHz) for 5 weeks starting at 80 dB SPL in the first week and then increasing the level by 6 dB per week to a final level of 104 dB SPL. Auditory brainstem responses (ABR) were recorded before, during, and following the exposure to determine the amount of hearing loss. The noise induced threshold shift to continuous long-term exposure, defined as compound threshold shift (CTS), within and above 16-20 kHz increased with noise level at the rate of 1.82 dB threshold shift per dB of noise level (NL) above a critical level (C) of 77.2 dB SPL i.e. CTS = 1.82(NL-77.2). The normalized amplitude of the largest ABR peak measured at 100 dB SPL decreased at the rate of 3.1% per dB of NL above the critical level of 76.9 dB SPL, i.e., %ABR Reduction = 3.1%(NL-76.9). ABR thresholds measured >30 days post-exposure only partially recovered resulting in a permanent threshold shift of 30-40 dB along with severe hair cell loss in the basal, high-frequency region of the cochlea. In the rat, CTS increases with noise level with a slope similar to humans and chinchillas. The critical level (C) in the rat is similar to that of humans, but higher than that of chinchillas.