HoxA13 Regulates Phenotype Regionalization of Human Pregnant Myometrium.
BACKGROUND
Bipedalism separates humans from most other animal species, but results in significant physiologic challenges, particularly with respect to the maintenance of pregnancy and induction of parturition. A contracted lower uterine segment (LUS) and a relaxed uterine fundal myometrium (FUN) during pregnancy are required to prevent pressure on the cervix from the fetal head due to gravity. With the onset of labor, this regionalization of myometrial function must be reversed, allowing descent of the fetus, dilation of the cervix, and expulsion of the fetus through the birth canal. However, the molecular mechanisms remain unclear.


OBJECTIVE
This study sought to identify phenotypic regionalization of LUS and FUN during pregnancy, RNA sequencing was performed to analyze the human myometrial transcriptome. Real-time PCR and immunoblotting were applied to validate sequencing results. Cell contraction/adhesion assays and gene microarrays were used to study the cellular functions of the identified genes.


RESULTS
Homeobox A13 (HoxA13), prostacyclin synthase (PTGIS), and periostin (POSTN) genes are more highly expressed in LUS than FUN of nonlaboring, but not laboring, myometrial cells at term. HoxA13 up-regulates transcription of PTGIS and POSTN genes. Elevated HoxA13 expression enhances myometrial cell contractility and cell-cell adhesion. Gene microarray studies show that HoxA13-regulated genes are associated with immune response, gap junction/cell adhesion, and pregnancy.


CONCLUSIONS
The LUS expresses higher levels of HoxA13, PTGIS, and POSTN, and is more contractile than the FUN at term prior to labor. This pregnancy-maintaining regionalization of myometrial function may be mediated by HoxA13.
Vancouver Prostate Centre (L.L., H.L., X.D.), Department of Urologic Sciences, University of British Columbia, Vancouver V6H 3Z6, Canada; BC Cancer Agency (D.D., S.J.M.J.), Genome Sciences Center, Vancouver V5Z 4S6, Canada; Department of Molecular Biology and Biochemistry (D.D., S.J.M.J.), Simon Fraser University, Burnaby V5A 1S6, Canada; Department of Obstetrics and Gynaecology (O.S., S.J.L., X.D.), University of Toronto, Toronto M5G 1E2, Canada; Department of Physiology & Pharmacology (D.S.), University of Calgary, Calgary T2N 4N1, Canada; and Department of Medical Genetics (S.J.M.J), University of British Columbia, Vancouver V6T 1Z3, Canada.
LiangLiang
L
Liu
Vancouver Prostate Centre (L.L., H.L., X.D.), Department of Urologic Sciences, University of British Columbia, Vancouver V6H 3Z6, Canada; BC Cancer Agency (D.D., S.J.M.J.), Genome Sciences Center, Vancouver V5Z 4S6, Canada; Department of Molecular Biology and Biochemistry (D.D., S.J.M.J.), Simon Fraser University, Burnaby V5A 1S6, Canada; Department of Obstetrics and Gynaecology (O.S., S.J.L., X.D.), University of Toronto, Toronto M5G 1E2, Canada; Department of Physiology & Pharmacology (D.S.), University of Calgary, Calgary T2N 4N1, Canada; and Department of Medical Genetics (S.J.M.J), University of British Columbia, Vancouver V6T 1Z3, Canada.
Haolong
H
Li
Vancouver Prostate Centre (L.L., H.L., X.D.), Department of Urologic Sciences, University of British Columbia, Vancouver V6H 3Z6, Canada; BC Cancer Agency (D.D., S.J.M.J.), Genome Sciences Center, Vancouver V5Z 4S6, Canada; Department of Molecular Biology and Biochemistry (D.D., S.J.M.J.), Simon Fraser University, Burnaby V5A 1S6, Canada; Department of Obstetrics and Gynaecology (O.S., S.J.L., X.D.), University of Toronto, Toronto M5G 1E2, Canada; Department of Physiology & Pharmacology (D.S.), University of Calgary, Calgary T2N 4N1, Canada; and Department of Medical Genetics (S.J.M.J), University of British Columbia, Vancouver V6T 1Z3, Canada.
Daryanaz
D
Dargahi
Vancouver Prostate Centre (L.L., H.L., X.D.), Department of Urologic Sciences, University of British Columbia, Vancouver V6H 3Z6, Canada; BC Cancer Agency (D.D., S.J.M.J.), Genome Sciences Center, Vancouver V5Z 4S6, Canada; Department of Molecular Biology and Biochemistry (D.D., S.J.M.J.), Simon Fraser University, Burnaby V5A 1S6, Canada; Department of Obstetrics and Gynaecology (O.S., S.J.L., X.D.), University of Toronto, Toronto M5G 1E2, Canada; Department of Physiology & Pharmacology (D.S.), University of Calgary, Calgary T2N 4N1, Canada; and Department of Medical Genetics (S.J.M.J), University of British Columbia, Vancouver V6T 1Z3, Canada.
Oksana
O
Shynlova
Vancouver Prostate Centre (L.L., H.L., X.D.), Department of Urologic Sciences, University of British Columbia, Vancouver V6H 3Z6, Canada; BC Cancer Agency (D.D., S.J.M.J.), Genome Sciences Center, Vancouver V5Z 4S6, Canada; Department of Molecular Biology and Biochemistry (D.D., S.J.M.J.), Simon Fraser University, Burnaby V5A 1S6, Canada; Department of Obstetrics and Gynaecology (O.S., S.J.L., X.D.), University of Toronto, Toronto M5G 1E2, Canada; Department of Physiology & Pharmacology (D.S.), University of Calgary, Calgary T2N 4N1, Canada; and Department of Medical Genetics (S.J.M.J), University of British Columbia, Vancouver V6T 1Z3, Canada.
Donna
D
Slater
Vancouver Prostate Centre (L.L., H.L., X.D.), Department of Urologic Sciences, University of British Columbia, Vancouver V6H 3Z6, Canada; BC Cancer Agency (D.D., S.J.M.J.), Genome Sciences Center, Vancouver V5Z 4S6, Canada; Department of Molecular Biology and Biochemistry (D.D., S.J.M.J.), Simon Fraser University, Burnaby V5A 1S6, Canada; Department of Obstetrics and Gynaecology (O.S., S.J.L., X.D.), University of Toronto, Toronto M5G 1E2, Canada; Department of Physiology & Pharmacology (D.S.), University of Calgary, Calgary T2N 4N1, Canada; and Department of Medical Genetics (S.J.M.J), University of British Columbia, Vancouver V6T 1Z3, Canada.
Steven J M
SJ
Jones
Vancouver Prostate Centre (L.L., H.L., X.D.), Department of Urologic Sciences, University of British Columbia, Vancouver V6H 3Z6, Canada; BC Cancer Agency (D.D., S.J.M.J.), Genome Sciences Center, Vancouver V5Z 4S6, Canada; Department of Molecular Biology and Biochemistry (D.D., S.J.M.J.), Simon Fraser University, Burnaby V5A 1S6, Canada; Department of Obstetrics and Gynaecology (O.S., S.J.L., X.D.), University of Toronto, Toronto M5G 1E2, Canada; Department of Physiology & Pharmacology (D.S.), University of Calgary, Calgary T2N 4N1, Canada; and Department of Medical Genetics (S.J.M.J), University of British Columbia, Vancouver V6T 1Z3, Canada.
Stephen J
SJ
Lye
Vancouver Prostate Centre (L.L., H.L., X.D.), Department of Urologic Sciences, University of British Columbia, Vancouver V6H 3Z6, Canada; BC Cancer Agency (D.D., S.J.M.J.), Genome Sciences Center, Vancouver V5Z 4S6, Canada; Department of Molecular Biology and Biochemistry (D.D., S.J.M.J.), Simon Fraser University, Burnaby V5A 1S6, Canada; Department of Obstetrics and Gynaecology (O.S., S.J.L., X.D.), University of Toronto, Toronto M5G 1E2, Canada; Department of Physiology & Pharmacology (D.S.), University of Calgary, Calgary T2N 4N1, Canada; and Department of Medical Genetics (S.J.M.J), University of British Columbia, Vancouver V6T 1Z3, Canada.
Xuesen
X
Dong
D000328:Adult; D002448:Cell Adhesion / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005260:Female; D017629:Gap Junctions / Q000235:genetics; D005865:Gestational Age; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D009119:Muscle Contraction / Q000235:genetics; D009215:Myometrium / Q000033:anatomy & histology*; D010641:Phenotype; D011247:Pregnancy; D012313:RNA / Q000235:genetics; D014590:Uterine Contraction / Q000235:genetics
D015815:Cell Adhesion Molecules; D018398:Homeodomain Proteins; C512835:POSTN protein, human; C099959:homeobox protein HOXA13; D012313:RNA; D003577:Cytochrome P-450 Enzyme System; C472456:PTGIS protein, human