H. Scott Stadler, Ph.D.
3101 SW Sam Jackson Park Road
Portland, OR 97239
HOX protein transcriptome
I am intensely interested in understanding the transcriptomes regulated by HOXA13 and HOXD13 in mice and humans. Our research ranges from biochemical identification of the DNA sequences preferred by individual HOX proteins to the development of therapeutics aimed at augmenting deficiencies in target gene expression caused by the loss of HOX protein function.
Additionally, our research is focused on discerning the molecular mechanisms required for the repair and regeneration of bone, cartilage, and genitourinary tissues. To identify the molecular signals necessary to direct the repair and possibly the regeneration of these tissues, I have focused on dissecting the transcriptional pathways regulated by HOXA13 and HOXD13. In humans and mice, mutations in HOXA13 and HOXD13 affect the growth and formation of virtually all skeletal tissues in the hand and foot as well as the normal development of the penis, uterus, cervix, ureter, and bladder. Recognizing the essential role these transcription factors have in the formation of these tissues, my central hypothesis is that HOXA13 and HOXD13 can be used as genetic anchor points to identify upstream and downstream factors necessary to instruct cells to form skeletal tissues. As the genes regulated by HOXA13 and HOXD13 in the hand and foot are defined, these target gene products will be used to instruct nascent- or induced-pluripotent stem cells (IPSCs) to repair or regenerate tissues impacted by injury, disease, or congenital malformation.
Identification of a novel long non coding RNA and its development as a pro-chondrogenic therapeutic Analysis of the long non coding RNA (LNC-RNA), HOTCHON, identified by our group, suggests an essential role in coordinating the genes necessary for chondrogenesis. We are currently evaluating the instructive capacity of this LNC-RNA to direct pluripotent cells to form cartilage and/or skeletal elements in adult mice and in a defined three dimensional matrix cell culture system. A primary complication in surgeries affecting cartilage or skeletal tissues is the relatively slow healing capacity of the tissues. To address this issue, the HOTCHON LNC-RNA will be evaluated in mice for its capacity to promote de novo chondrogenesis with the hope that HUMAN HOTCHON could be used to improve cartilage healing in patients.
Chemical Biology: I have also used the HOXA13 DNA binding assay to identify small molecules that inhibit HOXA13 DNA binding. This research was supported by the Broad Institute at MIT, and has led to the successful funding of my R01 application to the National Cancer Institute. We are currently developing several HOXA13 and HOXD13 antagonists that are being assessed for a role in blocking tumor promoting functions of HOXA13 and HOXD13. Recognizing that HOXA13 and HOXD13 primarily function to coordinate the genes necessary for skeletal development, I am also characterizing whether these compounds may be useful to treat orthopedic conditions involving excessive bone/cartilage growth such as Fibrodysplasia Ossificans Progressiva, a rare disorder causing excessive bone growth.
Morgan, E.A., Nguyen, S.B., Scott, V., and Stadler, H.S. Loss of Bmp7 and Fgf8 signaling in Hoxa13-mutant mice causes hypospadia. Development 2003, 130:3095-3109
Stadler, H.S. Modeling genitourinary defects in mice: An emerging genetic and developmental system. Nature Reviews Genetics 2003, 4:478-482.
Knosp W.M., Scott, V., Bächinger, H.P., and Stadler H.S. HOXA13 directly regulates the expression of bone morphogenetic proteins 2 and 7 to control distal limb morphogenesis Development 2004 131:4581-4592.
Shou, S., Scott, V., Reed, C., Hintzemann, R., and Stadler H.S. Transcriptome analysis of the murine forelimb and hindlimb autopod. Dev. Dyn. 234(1):74-89, 2005
Knosp, W.M., Saneyoshi, C., Shou, S., Bächinger, H.P., Stadler, H.S., Elucidation, Quantitative Refinement, and In Vivo Utilization of the Hoxa13 DNA Binding Site., J. Biol Chem. 2007 Mar 2;282(9):6843-53
Shaut, C.A.E., Keene, D.R., Sorensen, L., Li, D.Y. and Stadler H.S, A novel role for HOXA13 in placental development and labyrinth endothelial specification, PLoS Genetics. 2008 May 16;4(5):e1000073. PMID: 18483557
Perez WD, Weller CR, Shou S, Stadler HS. Survival of Hoxa13 homozygous mutants reveals a novel role in digit patterning and appendicular skeletal development. Dev Dyn. 2010 Feb;239(2):446-57
Zhang Y, Larsen, CA, Stadler H.S., Ames, JBStructural basis for sequence specific DNA binding and protein dimerization of HOXA13. 2011 PloS One 6(8):e23069
Sheth R, Barozzi I, Langlais D, Osterwalder M, Nemec S, Carlson HL, Stadler HS, Visel A, Drouin J, Kmita M.Distal Limb Patterning Requires Modulation of cis-Regulatory Activities by HOX13. Cell Rep. 2016 Dec 13;17(11):2913-2926. doi: 10.1016/j.celrep.2016.11.039.
Kherdjemil Y, Lalonde RL, Sheth R, Dumouchel A, de Martino G, Pineault KM, Wellik DM, Stadler HS, Akimenko MA, Kmita M. Evolution of Hoxa11 regulation in vertebrates is linked to the pentadactyl state. Nature. 2016 Nov 3;539(7627):89-92. doi: 10.1038/nature19813. Epub 2016 Oct 5.
Carlson HL, Quinn JJ, Yang YW, Thornburg CK, Chang HY, Stadler HS. LncRNA-HIT Functions as an Epigenetic Regulator of Chondrogenesis through Its Recruitment of p100/CBP Complexes. PLoS Genet. 2015 Dec 3;11(12):e1005680. doi: 10.1371/journal.pgen.1005680. eCollection 2015 Dec.
Huang AH, Riordan TJ, Pryce B, Weibel JL, Watson SS, Long F, Lefebvre V, Harfe BD, Stadler HS, Akiyama H, Tufa SF, Keene DR, Schweitzer R. Musculoskeletal integration at the wrist underlies the modular development of limb tendons. Development. 2015 Jul 15;142(14):2431-41. doi: 10.1242/dev.122374. Epub 2015 Jun 10.
Turner M, Zhang Y, Carlson HL, Stadler HS, Ames JB. Chemical shift assignments of mouse HOXD13 DNA binding domain bound to duplex DNA. Biomol NMR Assign. 2015 Oct;9(2):267-70. doi: 10.1007/s12104-014-9589-4. Epub 2014 Dec 10.
Shou S, Carlson HL, Perez WD, Stadler HS. HOXA13 regulates Aldh1a2 expression in the autopod to facilitate interdigital programmed cell death. Dev Dyn. 2013 Jun;242(6):687-98. doi: 10.1002/dvdy.23966. Epub 2013 Apr 28.
Owens KM, Quinonez SC, Thomas PE, Keegan CE, Lefebvre N, Roulston D, Larsen CA, Stadler HS, Innis JW. Analysis of de novo HOXA13 polyalanine expansions supports replication slippage without repair in their generation. Am J Med Genet A. 2013 May;161A(5):1019-27. doi: 10.1002/ajmg.a.35843. Epub 2013 Mar 26.