Nicholas Fairbridge - Sept. 14, 2012

Developmental regulation by CECR2 chromatin remodeling

Embryogenesis is a crucial process that relies on a wide variety of regulatory controls to ensure cellular differentiation and the overall embryonic structure is established properly. Epigenetic control of cellular differentiation is emerging as predominant means by which the regulation and maintenance of cell fate is established. My interests focused on a newly discovered chromatin remodeling complex CERF, made up of a catalytic ATPase/helicase subunit thought to remodel the nucleosome/DNA interaction and a bromodomain-containing subunit proposed to bind and specify target regions. The CECR2 bromodomain-containing subunit of CERF was shown to be necessary for the proper development of the mouse embryonic neural tube and was expressed in a variety of developing organs.

We set out to establish what CECR2 remodeling was targeting during the mouse neurulation process. Microarray analysis of Cecr2 mutant embryos identified misregulated candidate genes that were known to manifest neural tube defects when disrupted (Alx1, Bmi1, Bmp2, Met, Dlx5, Mdm4, and Prrx1). The candidate list also showed an abundance of mesenchymal and epithelial transcription factors. Transcripts with altered expression clustered into enriched regions on chromosome 6A, 6F-G and chromosome 12B. The arrays suggested a process of mesenchymal-epithelial differentiation was disrupted through the misregulation of key transcription factors. CECR2 appeared to target specific, but broad, regions of chromatin.

As Cecr2 was expressed in a variety of organs other than the neural tube, another aim was to establish what the developmental role of CECR2 was in these regions, and whether they were associated with further Cecr2 developmental abnormalities. To this end, a new Cecr2 deletion allele was generated. Characterization of the Cecr2tm1.1Hemc mutation expanded the Cecr2-associated phenome to include midline facial clefts, encephaloceles, reduced adult brain weight, caudal vertebrae malformations, and a series of congenital abnormalities of the kidney and urinary tract all in addition to the prevalent neural tube defect.

CECR2 remodeling appears to regulate the condensation/differentiation of mesenchymal cells and their transition to epithelialized tubes. This process affects the regulation of a set of homeodomain transcription factors during neurulation; but, as an epigenetic regulator, the targets of CECR2 remodeling could change depending on the cell lineage.

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