An integrated transcriptomics-guided genome-wide promoter analysis and next-generation proteomics approach to mine factor(s) regulating cellular differentiation

Mandal, Kunal Kumar; Bader, Samuel L.; Kumar, Pankaj; Malakar, Dipankar; Campbell, D. S.; Pradhan, Bhola Shankar; Sarkar, Rajesh; Wadhwa, Neerja; Sensharma, Souvik; Jain, Vaibhav; Moritz, Robert L.; Majumdar, Subeer S.

doi:10.1093/dnares/dsw057

Cited by 6 publications

(7 citation statements)

References 48 publications

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“…Microarray is a powerful technique to study differentially expressed genes in large numbers [ 11 ]. Differential gene expression during spermatogenesis has been studied by various researchers using microarray technology studied by us [ 12 , 13 ] and others [ 14 – 16 ]. These gene expression profiling experiments reveal candidate genes for the regulation of spermatogenesis and fertility as well as targets for innovative contraceptives that act on gene products absent in other somatic tissues.…”

Section: Introductionmentioning

confidence: 99%

Hormone induced differential transcriptome analysis of Sertoli cells during postnatal maturation of rat testes

et al. 2018

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Sertoli cells (Sc) are unique somatic cells of testis that are the target of both FSH and testosterone (T) and regulate spermatogenesis. Although Sc of neonatal rat testes are exposed to high levels of FSH and T, robust differentiation of spermatogonial cells becomes conspicuous only after 11-days of postnatal age. We have demonstrated earlier that a developmental switch in terms of hormonal responsiveness occurs in rat Sc at around 12 days of postnatal age during the rapid transition of spermatogonia A to B. Therefore, such “functional maturation” of Sc, during pubertal development becomes prerequisite for the onset of spermatogenesis. However, a conspicuous difference in robust hormone (both T and FSH) induced gene expression during the different phases of Sc maturation restricts our understanding about molecular events necessary for the spermatogenic onset and maintenance. Here, using microarray technology, we for the first time have compared the differential transcriptional profile of Sc isolated and cultured from immature (5 days old), maturing (12 days old) and mature (60 days old) rat testes. Our data revealed that immature Sc express genes involved in cellular growth, metabolism, chemokines, cell division, MAPK and Wnt pathways, while mature Sc are more specialized expressing genes involved in glucose metabolism, phagocytosis, insulin signaling and cytoskeleton structuring. Taken together, this differential transcriptome data provide an important resource to reveal the molecular network of Sc maturation which is necessary to govern male germ cell differentiation, hence, will improve our current understanding of the etiology of some forms of idiopathic male infertility.

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Section: Introductionmentioning

confidence: 99%

Hormone induced differential transcriptome analysis of Sertoli cells during postnatal maturation of rat testes

et al. 2018

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“…In the present study, we demonstrate a role of homeobox transcription factor MEIS1 in maturation of Sc and, hence, spermatogenesis. We selected Meis1 from the list of transcription factors whose binding sites were found by us to be enriched in the genes which gets up‐regulated in Sc during puberty 16 . As the binding sites of MEIS1 are significantly enriched on the promoter of genes up‐regulated in pubertal Sc, we hypothesized that MEIS1 could be playing an important role in regulating pubertal Sc function which is also associated with robust Gc differentiation, first time after birth.…”

Section: Discussionmentioning

confidence: 99%

“…In a previously reported study from our laboratory, the binding sites of a number of TFs in genes up‐regulated in mature Sc and infant (immature) Sc were identified using TRANSFAC analysis 16 . Analysis of the TRANSFAC data revealed that the binding site for the transcription factor MEIS1 was significantly enriched on the promoters of the genes up‐regulated in functionally mature pubertal Sc.…”

Section: Introductionmentioning

confidence: 98%

Homeobox transcription factor Meis1 is crucial to Sertoli cell mediated regulation of male fertility

et al. 2020

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Background Infertility has become a global phenomenon and constantly declining sperm count in males in modern world pose a major threat to procreation of humans. Male fertility is critically dependent on proper functioning of testicular Sertoli cells. Defective Sertoli cell proliferation and/or impaired functional maturation may be one of the underlying causes of idiopathic male infertility. Using high‐throughput “omics” approach, we found binding sites for homeobox transcription factor MEIS1 on the promoters of several genes up‐regulated in pubertal (mature) Sertoli cells, indicating that MEIS1 may be crucial for Sertoli cell‐mediated regulation of spermatogenesis at and after puberty. Objective To decipher the role of transcription factor MEIS1 in Sertoli cell maturation and spermatogenesis. Materials and methods Sc‐specific Meis1 knockdown (KD) transgenic mice were generated using pronuclear microinjection. Morphometric and histological analysis of the testes from transgenic mice was performed to identify defects in spermatogenesis. Epididymal sperm count and litter size were analyzed to determine the effect of Meis1 knockdown on fertility. Results Sertoli cell (Sc)‐specific Meis1 KD led to massive germ cell loss due to apoptosis and impaired spermatogenesis. Unlike normal pubertal Sc, the levels of SOX9 in pubertal Sc of Meis1 KD were significantly high, like immature Sc. A significant reduction in epididymal sperm count was observed in these mice. The mice were found to be infertile or sub‐fertile (with reduced litter size), depending on the extent of Meis1 inhibition. Discussion The results of this study demonstrated for the first time, a role of Meis1 in Sc maturation and normal spermatogenic progression. Inhibition of Meis1 in Sc was associated with deregulated spermatogenesis and a consequent decline in fertility of the transgenic mice. Conclusions Our results provided substantial evidence that suboptimal Meis1 expression in Sc may be one of the underlying causes of idiopathic infertility.

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“…Another intriguing question that still remains unanswered is how this switch gets established during the juvenile period when the levels of circulating gonadotropins are barely minimal. It is also reasonable to consider that the compromised maturation of Sertoli cells may lead to impaired functioning of these cells with insufficient expression of genes important for regulation of spermatogenesis, as has been shown by us (Das et al, 2013;Mandal et al, 2017). Such a situation may not allow the Sertoli cells to efficiently augment germ cell proliferation and differentiation, even in the phase of elevated hormones, which manifest at puberty.…”

Section: Pubertal Maturation Of Testis Leading To the Spermatogenicmentioning

confidence: 99%

“…This was coupled with high throughput proteomics (like SWATH analysis etc.) to identify factors in infant and pubertal Sertoli cells which are crucial for spermatogenesis (Mandal et al, ). The new information will significantly improve our current understanding of the etiology of some forms of pubertal defects leading to idiopathic male infertility.…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Pubertal orchestration of hormones and testis in primates

Bhattacharya

Sharma

Majumdar

2019

Molecular Reproduction Devel

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The term “Puberty”, socially known as “Adolescence” is the transitional period from juvenile life to adulthood with functional maturation of gonads and genital organs. In this process, some remarkable developmental changes occur in morphology, physiology, and behavior leading to reproductive competence. Despite sufficient levels of gonadotropins (luteinizing hormone [LH] and follicle‐stimulating hormone [FSH]), robust spermatogenesis is not initiated during infancy in primates due to the immaturity of testicular Sertoli cells. Recent studies suggest that developmental competence augmenting functional activities of receptors for androgen and FSH is acquired by Sertoli cells somewhere during the prolonged hypo‐gonadotropic juvenile period. This juvenile phase is terminated with the re‐awakening of hypothalamic Kisspeptin/Neurokinin B/Dynorphin neurons which induce the release of the gonadotropin‐releasing hormone leading to reactivation of the hypothalamo‐pituitary‐testicular axis at puberty. During this period of pubertal development, FSH and LH facilitate further maturation of testicular cells (Sertoli cells and Leydig cells) triggering robust differentiation of the spermatogonial cells, ensuing the spermatogenic onset. This review aims to precisely address the evolving concepts of the pubertal regulation of hormone production with the corresponding cooperation of testicular cells for the initiation of robust spermatogenesis, which can be truly called “testicular puberty.”

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An integrated transcriptomics-guided genome-wide promoter analysis and next-generation proteomics approach to mine factor(s) regulating cellular differentiation

Cited by 6 publications

References 48 publications

Hormone induced differential transcriptome analysis of Sertoli cells during postnatal maturation of rat testes

Hormone induced differential transcriptome analysis of Sertoli cells during postnatal maturation of rat testes

Homeobox transcription factor Meis1 is crucial to Sertoli cell mediated regulation of male fertility

Pubertal orchestration of hormones and testis in primates

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