Identifying genetic networks underlying myometrial transition to labor.
BACKGROUND
Early transition to labor remains a major cause of infant mortality, yet the causes are largely unknown. Although several marker genes have been identified, little is known about the underlying global gene expression patterns and pathways that orchestrate these striking changes.


RESULTS
We performed a detailed time-course study of over 9,000 genes in mouse myometrium at defined physiological states: non-pregnant, mid-gestation, late gestation, and postpartum. This dataset allowed us to identify distinct patterns of gene expression that correspond to phases of myometrial 'quiescence', 'term activation', and 'postpartum involution'. Using recently developed functional mapping tools (HOPACH (hierarchical ordered partitioning and collapsing hybrid) and GenMAPP 2.0), we have identified new potential transcriptional regulatory gene networks mediating the transition from quiescence to term activation.


CONCLUSIONS
These results implicate the myometrium as an essential regulator of endocrine hormone (cortisol and progesterone synthesis) and signaling pathways (cyclic AMP and cyclic GMP stimulation) that direct quiescence via the transcriptional upregulation of both novel and previously associated regulators. With term activation, we observe the upregulation of cytoskeletal remodeling mediators (intermediate filaments), cell junctions, transcriptional regulators, and the coordinate downregulation of negative control checkpoints of smooth muscle contractile signaling. This analysis provides new evidence of multiple parallel mechanisms of uterine contractile regulation and presents new putative targets for regulating myometrial transformation and contraction.
Salomonis
Nathan
N
Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA.
Cotte
Nathalie
N
Zambon
Alexander C
AC
Pollard
Katherine S
KS
Vranizan
Karen
K
Doniger
Scott W
SW
Dolganov
Gregory
G
Conklin
Bruce R
BR
D000818:Animals; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005865:Gestational Age; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D009215:Myometrium / Q000378:metabolism*; D036801:Parturition; D049590:Postpartum Period / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014590:Uterine Contraction / Q000235:genetics* / Q000378:metabolism
D012333:RNA, Messenger; D020962:Heterotrimeric GTP-Binding Proteins