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Title: A unique stylopod patterning mechanism by Shox2-controlled osteogenesis

Here, vertebrate appendage patterning is programmed by Hox-TALE factorbound regulatory elements. However, it remains unclear which cell lineages are commissioned by Hox-TALE factors to generate regional specific patterns and whether other Hox-TALE co-factors exist. In this study, we investigated the transcriptional mechanisms controlled by the Shox2 transcriptional regulator in limb patterning. Harnessing an osteogenic lineage-specific Shox2 inactivation approach we show that despite widespread Shox2 expression in multiple cell lineages, lack of the stylopod observed upon Shox2 deficiency is a specific result of Shox2 loss of function in the osteogenic lineage. ChIP-Seq revealed robust interaction of Shox2 with cis-regulatory enhancers clustering around skeletogenic genes that are also bound by Hox-TALE factors, supporting a lineage autonomous function of Shox2 in osteogenic lineage fate determination and skeleton patterning. Pbx ChIP-Seq further allowed the genome-wide identification of cis-regulatory modules exhibiting co-occupancy of Pbx, Meis and Shox2 transcriptional regulators. Integrative analysis of ChIP-Seq and RNA-Seq data and transgenic enhancer assays indicate that Shox2 patterns the stylopod as a repressor via interaction with enhancers active in the proximal limb mesenchyme and antagonizes the repressive function of TALE factors in osteogenesis.
Authors:
 [1] ;  [2] ;  [2] ;  [3] ;  [4] ;  [5] ;  [4] ;  [4] ;  [2] ;  [1] ;  [1] ;  [6] ;  [6] ;  [7] ;  [8] ;  [4] ; ORCiD logo [2]
  1. Tulane Univ., New Orleans, LA (United States)
  2. Tulane Univ., New Orleans, LA (United States); Fujian Normal Univ., Fujian (People's Republic of China)
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  4. Univ. of Calgary, Calgary, AB (Canada)
  5. Tulane Univ., New Orleans, LA (United States); Sichuan Univ., Sichuan (People's Republic of China)
  6. Icahn School of Medicine at Mount Sinai, New York, NY (United States)
  7. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States); Univ. of California, Merced, CA (United States)
  8. Fujian Normal Univ., Fujian (People's Republic of China)
Publication Date:
Grant/Contract Number:
AC02-05CH11231
Type:
Accepted Manuscript
Journal Name:
Development (Cambridge)
Additional Journal Information:
Journal Name: Development (Cambridge); Journal Volume: 143; Journal Issue: 14; Journal ID: ISSN 0950-1991
Publisher:
Company of Biologists
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Limb; Patterning; Shox2; Skeleton; Stylopod
OSTI Identifier:
1393061