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Gene cross-talk is key to a cell's balance
There is evidence of direct cross-talk between the regulatory genes Nanog and Hox, according to a study published online June 5, 2017, in the Proceedings of the National Academy of Sciences (PNAS), by Stowers scientists Bony De Kumar PhD and Robb Krumlauf PhD, Department of Anatomy & Cell Biology, The University of Kansas School of Medicine.
In adult organisms, striking a balance between two states is important to keep many tissues in equilibrium. For example, our blood supply has cells that are differentiating, dying, or being repaired — while a reserve population of blood-producing adult stem cells is waiting until needed to help replace them.
"Parents may say, 'You need to get good grades; you need to learn this,' for positive guidance but they are just as likely to reinforce the importance of that advice and minimize negative outcomes by adding, 'You don't want to do that,'" explains Robb Krumlauf PhD, Scientific Director and Professor, Department of Anatomy & Cell Biology, University of Kansas School of Medicine; Professor, Neurosciences Graduate Program; Professor, Department of Oral Biology, University of Missouri at Kansas City Dental School.
Both positive and negative instructions are important. Nanog and Hox genes have their own distinct jobs. Yet through inhibiting each other, they are also balance their cell states, helping the cell keep on course.
"Differentiation and pluripotency are well-studied processes. This paper actually links the two processes. Before, we didn't know these pathways were actively talking to each other. It was pretty surprising for us."
The researchers made the discovery while studying Hox genes in the early stages of mouse embryonic stem cell differentiation. Hox are "architect genes" controlling the layout of the developing embryo. They play a key role in establishing the basic body plan and craniofacial development of the embryo.
At two hours and 12 hours of retinoic acid treatment, researchers found that both Hox and Nanog genes bound to many of the same target sites in a cell. This suggests regulatory cross-talk between both pluripotency and differentiation pathways regulated by these two genes. Researchers also observed that Hox and Nanog also repress each other depending on the context in which they are found. Their findings paint a picture of cell states that are more plastic than fixed.
Krumlauf and De Kumar's work provides important insight into the basic processes of tissue formation, relevant to the field of regenerative medicine and the development of therapeutic approaches for certain cancers.
Homeobox a1 (Hoxa1) is one of the most rapidly induced genes in ES cell differentiation and it is the earliest expressed Hox gene in the mouse embryo. In this study, we used genomic approaches to identify Hoxa1-bound regions during early stages of ES cell differentiation into the neuro-ectoderm. Within 2 h of retinoic acid treatment, Hoxa1 is rapidly recruited to target sites that are associated with genes involved in regulation of pluripotency, and these genes display early changes in expression. The pattern of occupancy of Hoxa1 is dynamic and changes over time. At 12 h of differentiation, many sites bound at 2 h are lost and a new cohort of bound regions appears. At both time points the genome-wide mapping reveals that there is significant co-occupancy of Nanog (Nanog homeobox) and Hoxa1 on many common target sites, and these are linked to genes in the pluripotential regulatory network. In addition to shared target genes, Hoxa1 binds to regulatory regions of Nanog, and conversely Nanog binds to a 3? enhancer of Hoxa1. This finding provides evidence for direct cross-regulatory feedback between Hoxa1 and Nanog through a mechanism of mutual repression. Hoxa1 also binds to regulatory regions of Sox2 (sex-determining region Y box 2), Esrrb (estrogen-related receptor beta), and Myc, which underscores its key input into core components of the pluripotential regulatory network. We propose a model whereby direct inputs of Nanog and Hoxa1 on shared targets and mutual repression between Hoxa1 and the core pluripotency network provides a molecular mechanism that modulates the fine balance between the alternate states of pluripotency and differentiation.
Key word search: gene regulation Hox genes pluripotency Nanog regulatory networks.
Additional contributors: Hugo J. Parker, Mark E. Parrish, Jeffrey J. Lange, Brian D. Slaughter, Jay R. Unruha, Ariel Paulson
The authors declare no conflict of interest.
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The bright green spot is Nanog mRNA being transcribed or "read" in the cell nucleus.
Dim green spots are stable Nanog elswehere in the cell.
Image credit: Bony De Kumar PhD, and Robb Krumlauf PhD.