Modifications at the N-terminal tails of nucleosomal histones are required for efficient transcription in vivo. We analyzed how H3 histone methylation and demethylation control expression of estrogen-responsive genes and show that a DNA-bound estrogen receptor directs transcription by participating in bending chromatin to contact the RNA polymerase II recruited to the promoter. This process is driven by receptor-targeted demethylation of H3 lysine 9 at both enhancer and promoter sites and is achieved by activation of resident LSD1 demethylase. Localized demethylation produces hydrogen peroxide, which modifies the surrounding DNA and recruits 8-oxoguanine-DNA glycosylase 1 and topoisomeraseIIbeta, triggering chromatin and DNA conformational changes that are essential for estrogen-induced transcription. Our data show a strategy that uses controlled DNA damage and repair to guide productive transcription.
We have found that 17-estradiol induces bcl-2 transcription in human breast cancer MCF-7 cells. To identify cis-acting elements involved in this regulation, we have analyzed hormone responsiveness of transiently transfected reporter constructs containing the bcl-2 major promoter (P 1 ). Hormone inducibility was observed only when either of two sequences, located within the bcl-2 coding region and showing one and two mutations with respect to the consensus estrogen-responsive element, were inserted downstream from the P 1 promoter. Both sequences behaved as enhancers exclusively in cells expressing the estrogen receptor and were able to bind this receptor in in vitro assays. Transfections into MCF-7 cells of plasmids carrying a bcl-2 cDNA fragment which included these two elements revealed that their simultaneous presence resulted in an additive effect on reporter gene activity, whose size resembled the increase of endogenous bcl-2 mRNA level observed in untransfected cells after hormone treatment. Moreover, the identified elements were able to mediate up-regulation of bcl-2 expression by 17-estradiol, since exogenous bcl-2 mRNA was induced by hormone challenge of MCF-7 cells transiently transfected with a vector containing the bcl-2 coding sequence cloned under the control of a non-estrogen-responsive promoter. Finally, we show that hormone prevention of apoptosis, induced by incubating MCF-7 cells with hydrogen peroxide, was strictly related to bcl-2 up-regulation. Our results indicate that the bcl-2 major promoter does not contain cis-acting elements directly involved in transcriptional control by 17-estradiol and that hormone treatment inhibits programmed cell death in MCF-7 cells, inducing bcl-2 expression via two estrogen-responsive elements located within its coding region.
Transcriptional activation of the cyclin D1 gene (CCND1) plays a pivotal role in G 1 -phase progression, which is thereby controlled by multiple regulatory factors, including nuclear receptors (NRs). Appropriate CCND1 gene activity is essential for normal development and physiology of the mammary gland, where it is regulated by ovarian steroids through a mechanism(s) that is not fully elucidated. We report here that CCND1 promoter activation by estrogens in human breast cancer cells is mediated by recruitment of a c-Jun/c-Fos/estrogen receptor ␣ complex to the tetradecanoyl phorbol acetate-responsive element of the gene, together with Oct-1 to a site immediately adjacent. This process coincides with the release from the same DNA region of a transcriptional repressor complex including Yin-Yang 1 (YY1) and histone deacetylase 1 and is sufficient to induce the assembly of the basal transcription machinery on the promoter and to lead to initial cyclin D1 accumulation in the cell. Later on in estrogen stimulation, the cyclin D1/Cdk4 holoenzyme associates with the CCND1 promoter, where E2F and pRb can also be found, contributing to the long-lasting gene enhancement required to drive G 1 -phase completion. Interestingly, progesterone triggers similar regulatory events through its own NRs, suggesting that the gene regulation cascade described here represents a crossroad for the transcriptional control of G 1 -phase progression by different classes of NRs.Mammary gland morphogenesis and development result from the interplay of genetic and epigenetic pathways, controlled by hormones, growth factors, and other signaling molecules. Derangement of one or more of these regulatory pathways results in the abnormal growth and differentiation of mammary epithelial cells, leading to breast carcinogenesis. The ovarian hormones estrogen and progesterone promote mammary gland differentiation toward the female phenotype at the onset of puberty and control breast tropism and function throughout the reproductive life by affecting epithelial cell proliferation. Mammary gland cells are endowed with highaffinity receptors for these steroids (estrogen receptor ␣ [ER␣] and ER and progesterone receptor A [PR-A] and PR-B, respectively), which belong to the nuclear receptor (NR) family of transcription factors (31
Varicocele has been implicated as a cause in 35%-50% of patients with primary infertility and up to 81% of men with secondary infertility. Although a large number of reports have shown improvement in the semen parameters after correction of varicocele, other studies have suggested no benefit. We report the first case of azoospermia after surgery in a young infertile male patient with left-sided varicocele and severe oligozoospermia undergoing laparoscopic varicocelectomy. A pregnancy was only achieved with assisted reproductive technology because semen cryopreservation was performed before surgery. In the light of the above, the deterioration of sperm count after varicocele repair in patients with severe oligozoospermia could be due to irreversible impairment of spermatogenesis of such patients, together with the possible temporary damage of the surgical repair. This possible complication could therefore turn the severe oligozoospermia into an indication to perform cryopreservation before surgery, on both clinical and medico-legal grounds. Further research is needed before drawing definitive conclusions regarding the management of varicocele-related severe oligozoospermia.
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