Biology subjects

Salama, S. R.

Publications and source records attributed to Salama, S. R..

3 recordsLinked to original sources

bioRxiv2017

Structurally conserved primate lncRNAs are transiently expressed during human cortical differentiation and influence cell type specific genes

The cerebral cortex has expanded in size and complexity in primates, yet the underlying molecular mechanisms are obscure. We generated cortical organoids from human, chimpanzee, orangutan, and rhesus pluripotent stem cells and sequenced their transcriptomes at weekly time points for comparative analysis. We used transcript structure and expression conservation to discover thousands of expressed long non-coding RNAs (lncRNAs). Of 2,975 human, multi-exonic lncRNAs, 2,143 were structurally conserved to chimpanzee, 1,731 to orangutan, and 1,290 to rhesus. 386 human lncRNAs were transiently expressed (TrEx) and a similar expression pattern was often observed in great apes (46%) and rhesus (31%). Many TrEx lncRNAs were associated with neuroepithelium, radial glia, or Cajal-Retzius cells by single cell RNA-sequencing. 3/8 tested by ectopic expression showed [≥]2-fold effects on neural genes. This rich resource of primate expression data in early cortical development provides a framework for identifying new, potentially functional lncRNAs.

neuroscience↗

bioRxiv2017

Human-specific NOTCH-like genes in a region linked to neurodevelopmental disorders affect cortical neurogenesis

Genetic changes causing dramatic brain size expansion in human evolution have remained elusive. Notch signaling is essential for radial glia stem cell proliferation and a determinant of neuronal number in the mammalian cortex. We find three paralogs of human-specific NOTCH2NL are highly expressed in radial glia cells. Functional analysis reveals different alleles of NOTCH2NL have varying potencies to enhance Notch signaling by interacting directly with NOTCH receptors. Consistent with a role in Notch signaling, NOTCH2NL ectopic expression delays differentiation of neuronal progenitors, while deletion accelerates differentiation. NOTCH2NL genes provide the breakpoints in typical cases of 1q21.1 distal deletion/duplication syndrome, where duplications are associated with macrocephaly and autism, and deletions with microcephaly and schizophrenia. Thus, the emergence of hominin-specific NOTCH2NL genes may have contributed to the rapid evolution of the larger hominin neocortex accompanied by loss of genomic stability at the 1q21. 1 locus and a resulting recurrent neurodevelopmental disorder.

neuroscience↗

bioRxiv2017

Distinct epigenetic shift in a subset of Glioma CpG island methylator phenotype (G-CIMP) during tumor recurrence

Histomorphology and current grading schemes are unable to predict glioma relapse and malignant tumor progression. We reported that the IDH-mutant associated Glioma-CpG Island Methylator Phenotype (G-CIMP) can be further divided into two clinically distinct subtypes independent of histopathological grading (G-CIMP-high and -low) with evidence of correlation with tumor progression. Here we performed a comprehensive epigenomic analysis of 74 longitudinally collected glioma samples (grade II-IV) to understand malignant recurrence from G-CIMP-high to G-CIMP-low. G-CIMP-low recurrence appeared in 12% of all gliomas and resemble IDH-wildtype primary glioblastoma. G-CIMP-low recurrence can be characterized by distinct epigenetic changes at candidate functional tissue enhancers with AP-1/SOX binding elements, stem cell-like epigenomic phenotype, and genomic instability. Finally, we defined a set of candidate biomarker signatures that predict recurrence of G-CIMP-low with clinically relevance on patient outcomes. Our study provides opportunity for refined clinical trial designs and therapeutic targets that limit progression to more aggressive G-CIMP-low phenotype.\n\nHIGHLIGHTSO_LIIndolent G-CIMP-high progresses to aggressive G-CIMP-low phenotype\nC_LIO_LIIncidence of G-CIMP-low recurrent tumors are 3 times greater than G-CIMP-low primary\nC_LIO_LIG-CIMP-low recurrent tumors share epigenomic features with IDH-wildtype primary GBM\nC_LIO_LIPredictive biomarkers of G-CIMP-low progression at primary diagnosis\nC_LI

cancer biology↗