Uterine microRNA signature and consequence of their dysregulation in uterine disorders

MicroRNA (miRNA) has emerged as key post-transcriptional regulator and through this mechanism control many normal developmental and physiological processes. Conversely, aberrant expression of some miRNAs has been correlated with various disorders, more specifically, development and progression of malignancy. Endometrium is a dynamic tissue which undergoes extensive cyclic changes in preparation for embryo implantation during reproductive years, as well as changes that occur following menopause, and establishment of benign and malignant uterine disorders. These processes are highly regulated by ovarian steroids and locally expressed genes in response to steroid hormone receptor-mediated signaling and include genes related to inflammatory reaction, apoptosis, cell-cycle progression, angiogenesis and tissue remodeling. Here we present an overview of our current understanding of uterine miRNA biogenesis and highlights their potential regulatory functions in cellular processes relevant to normal uterine physiological and pathological disorders such as endometriosis, dysfunctional uterine bleeding and endometrial cancer. Understanding the expression, regulation and functional aspects of miRNAs in uterine environment under normal and various disorders may lead to their potential utilization as diagnostic as well as therapeutic tool.

Uterine microRNA signature and consequence of their dysregulation in uterine disorders

MicroRNA (miRNA) has emerged as key post-transcriptional regulator and through this mechanism control many normal developmental and physiological processes. Conversely, aberrant expression of some miRNAs has been correlated with various disorders, more specifically, development and progression of malignancy. Endometrium is a dynamic tissue which undergoes extensive cyclic changes in preparation for embryo implantation during reproductive years, as well as changes that occur following menopause, and establishment of benign and malignant uterine disorders. These processes are highly regulated by ovarian steroids and locally expressed genes in response to steroid hormone receptor-mediated signaling and include genes related to inflammatory reaction, apoptosis, cell-cycle progression, angiogenesis and tissue remodeling. Here we present an overview of our current understanding of uterine miRNA biogenesis and highlights their potential regulatory functions in cellular processes relevant to normal uterine physiological and pathological disorders such as endometriosis, dysfunctional uterine bleeding and endometrial cancer. Understanding the expression, regulation and functional aspects of miRNAs in uterine environment under normal and various disorders may lead to their potential utilization as diagnostic as well as therapeutic tool.(AU)

Orphan nuclear receptor regulation of reproduction

Orphan nuclear receptors, those without known ligands, were discovered because of their structural similarity to the ligand-driven steroid and thyroid receptors. Since their characterization, many of the orphan receptors have been adopted, i.e., ligands, usually lipids or derived lipids, have been discovered. The orphan receptors are transcriptional regulators, functioning in the reproductive context to upregulate or suppress gene expression. By this means, the orphan receptors regulate a plethora of reproductive events. In the majority of cases, the effects are stimulatory, indeed, members of the NR2 family promote Leydig cell differentiation and testicular steroidogenesis, while those of the NR4 family regulate early gestation and placental formation. The NR5 family has two members, steroidogenic factor-1 (SF-1, NR5A1) and liver receptor homolog-1 (LRH-1, NR5A2). These receptors interact with the same DNA sequence and are believed to be constitutive transcription factors. Their effects are modulated by the repressive effects of the NR0 family of orphan receptors that comprise the short heterodimeric partner (SHP, NR0B2) and dosage-sensitive sex reversal adrenal hypoplasia congenital region on the X chromosome, gene 1 (DAX1, NROB1). SHP and DAX1 inhibit the interaction of LRH-1 and SF-1 with coactivators, thereby reducing their constitutive transcriptional effects. Overall, the orphan nuclear receptors are essential regulators of reproductive function in mammals.

Orphan nuclear receptor regulation of reproduction

Orphan nuclear receptors, those without known ligands, were discovered because of their structural similarity to the ligand-driven steroid and thyroid receptors. Since their characterization, many of the orphan receptors have been adopted, i.e., ligands, usually lipids or derived lipids, have been discovered. The orphan receptors are transcriptional regulators, functioning in the reproductive context to upregulate or suppress gene expression. By this means, the orphan receptors regulate a plethora of reproductive events. In the majority of cases, the effects are stimulatory, indeed, members of the NR2 family promote Leydig cell differentiation and testicular steroidogenesis, while those of the NR4 family regulate early gestation and placental formation. The NR5 family has two members, steroidogenic factor-1 (SF-1, NR5A1) and liver receptor homolog-1 (LRH-1, NR5A2). These receptors interact with the same DNA sequence and are believed to be constitutive transcription factors. Their effects are modulated by the repressive effects of the NR0 family of orphan receptors that comprise the short heterodimeric partner (SHP, NR0B2) and dosage-sensitive sex reversal adrenal hypoplasia congenital region on the X chromosome, gene 1 (DAX1, NROB1). SHP and DAX1 inhibit the interaction of LRH-1 and SF-1 with coactivators, thereby reducing their constitutive transcriptional effects. Overall, the orphan nuclear receptors are essential regulators of reproductive function in mammals.(AU)