Anatomic Demarcation by Positional Variation in Fibroblast Gene Expression Programs
1 Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, California, United States of America,2 Department of Biochemistry, Stanford University School of Medicine, Stanford, California, United States of America, 3 Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, United States of America
Abstract
Fibroblasts are ubiquitous mesenchymal cells with many vital functions during development, tissue repair, and disease. Fibroblasts from different anatomic sites have distinct and characteristic gene expression patterns, but the principles that govern their molecular specialization are poorly understood. Spatial organization of cellular differentiation may be achieved by unique specification of each cell type; alternatively, organization may arise by cells interpreting their position along a coordinate system. Here we test these models by analyzing the genome-wide gene expression profiles of primary fibroblast populations from 43 unique anatomical sites spanning the human body. Large-scale differences in the gene expression programs were related to three anatomic divisions: anterior-posterior (rostral-caudal), proximal-distal, and dermal versus nondermal. A set of 337 genes that varied according to these positional divisions was able to group all 47 samples by their anatomic sites of origin. Genes involved in pattern formation, cell-cell signaling, and matrix remodeling were enriched among this minimal set of positional identifier genes. Many important features of the embryonic pattern of HOX gene expression were retained in fibroblasts and were confirmed both in vitro and in vivo. Together, these findings suggest that site-specific variations in fibroblast gene expression programs are not idiosyncratic but rather are systematically related to their positional identities relative to major anatomic axes.
Synopsis
A major question in developmental biology is, How do cells know where they are in the body? For example, skin cells on the scalp know to produce hair, and the skin cells on the palms of the hand know not to make hair. Overall, there are thousands of different cell types and each has a unique job that is important to overall organ function. It is critical that, as we grow and develop, each of these different cells passes on the proper function from generation to generation to maintain organ function. In this study, the authors present a model that explains how cells know where they are in the body. By comparing cells from 43 unique positions that finely map the entire human body, the authors discovered that cells utilize a ZIP-code system to identify the cell's position in the human body. The ZIP code for Stanford is 94305, and each digit hones in on the location of a place in the United States; similarly, cells know their location by using a code of genes. For example, a cell on the hand expresses a set of genes that locate the cell on the top half of the body (anterior) and another set of genes that locates the cell as being far away from the body or distal and a third set of genes that identifies the cell on the outside of the body (not internal). Thus, each set of genes narrows in on the cell's location, just like a ZIP code. These findings have important implications for the etiology of many diseases, wound healing, and tissue engineering.
Citation: Rinn JL, Bondre C, Gladstone HB, Brown PO, Chang HY (2006) Anatomic Demarcation by Positional Variation in Fibroblast Gene Expression Programs. PLoS Genet 2(7): e119. doi:10.1371/journal.pgen.0020119
Editor: Veronica van Heyningen, MRC Human Genetics Unit, United Kingdom
Received: May 1, 2006; Accepted: June 13, 2006; Published: July 28, 2006
Copyright: © 2006 Rinn et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Supported by grants from NIAMS/NIH (K08AR050007, HYC), NCI/NIH (RO1CA077097, POB), Howard Hughes Medical Institute (POB). JR is supported by the Damon Runyon Cancer Foundation Fellowship. POB is an investigator of the Howard Hughes Medical Institute. HYC is the Kenneth G. and Elaine A. Langone Scholar of the Damon Runyon Cancer Research Foundation.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: FDR, false discovery rate; SAM, Significance Analysis of Microarrays
* To whom correspondence should be addressed. E-mail: howchang@stanford.edu (HYC);pbrown@pmgm2.stanford.edu (POB)
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NOTA DESTE BLOGGER:
Como é que a célula sabe onde que ela está??? Para fazer isso usam um sistema tipo CEP (Código de Endereçamento Postal)??? Gente, isso é muita TELEOLOGIA em biologia vocês não acham? Ué, mas Darwin, o homem que teve a maior ideia que toda a humanidade já teve, não tinha eliminado a TELEOLOGIA de uma vez por todas em biologia? NADA MAIS FALSO!!!
