Editors' ChoiceMICROBIOTA

The Gut Is No Place for Freedom of Expression

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Science Translational Medicine  13 Nov 2013:
Vol. 5, Issue 211, pp. 211ec188
DOI: 10.1126/scitranslmed.3007979

Whereas Americans prize individual freedom, including the freedom of expression, gene expression must be carefully coordinated in tissues and cells if they are to function appropriately and survive. This is particularly true in the gut, where intestinal epithelial cells must work together as a continuously regenerating interface with billions of commensal bacteria. To coordinate gene expression, individual tissues and cells have enzymes that chemically modify histones and DNA to regulate chromatin structure and transcription—switching genes and pathways on and off in response to inherited and environmental cues. Among these enzymes, histone deacetylases (HDACs) have emerged as some of the most important because of their aberrant expression in many types of cancer and chronic disease and potential as therapeutic targets.

Alenghat and colleagues wanted to determine the functional role of HDAC3, a common HDAC subtype, in intestinal epithelial cells (IECs) in vivo. To do this, they generated mice with an IEC-specific HDAC3 deficiency and compared IEC gene expression, survival and proliferation, barrier function, and response to injury in HDAC3-deficient mice with wild-type mice. HDAC3 deletion was associated with altered gene expression involving multiple core cellular and IEC-specific pathways and abnormal IEC survival and proliferation. IEC barrier function was also impaired in HDAC3-deficient mice, and the response to injury was more prolonged and severe versus wild-type mice with normal HDAC3 expression. However, most effects of HDAC3 deficiency went away when HDAC3-deficient mice were rederived under germ-free conditions.

This study reveals a role for HDAC3 in coordinating the intestinal epithelial cell response to signals from the commensal microbiota and suggests that HDAC3 functions may be necessary to maintain normal host-microbiota relationships. Additional studies are needed to investigate the role and expression of HDAC3 in normal intestinal epithelial cells and the development of intestinal disease states plus the therapeutic response to natural and synthetic HDAC inhibitors.

T. Alenghat et al., Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis. Nature, published online 3 November 2013 (10.1038/nature12687). [Abstract]

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