Research Interests

Our studies are centered on the impact of gene regulatory circuits in normal development and disease.  

Our laboratory is interested in how transcriptional and post-transcriptional pathways impact normal development and how they are disrupted in disease. Our research interests overlap with the following fields:

  • RNA
  • Stem cell biology
  • Epigenetics
  • Reproductive biology
  • Developmental biology
  • Neurobiology 
  • Cancer

 

Molecular Mechanisms Driving Fertility.  Human infertility is extremely common (~15% of couples fail to conceive after 1 yr of unprotected sex) and many of these cases, particularly those in males, have unknown etiology.  A leading candidate to cure many forms of male infertility is spermatogonial stem cell (SSCs).  Our interest in SSCs was initiated when we discovered that the RHOX10 transcription factor is critical for the initial formation of SSCs during perinatal development in mice (Song et al. Cell Rep 2016). Picture 1We are currently investigating the underlying mechanisms by which RHOX10 acts.  We have also embarked on broader questions pertaining to SSCs through using single-cell RNA-seq (scRNAseq) analysis.  This has allowed us to define the developmental steps by which SSCs form in mice (Tan et al. Dev 2020) and humans (Sohni et al. Cell Rep 2019).  Towards the ultimate goal of developing “SSC therapy approaches” to treat male infertility, we have used scRNAseq analysis to identify undifferentiated spermatogonia subsets that have the molecular characteristic of SSCs (Sohni et al. Cell Rep 2019, Tan et al. Dev 2020). This goal has culminated most recently in the definitive identification of a highly enriched human SSC population (using xenograft germ-cell transplantation) bearing a specific cell-surface protein (Tan et al. PNAS 2020).  We have use these purified human SSCs to define approaches to both differentiate and culture undifferentiated spermatogonia with the characteristics of human SSCs (Tan et al. PNAS 2020).

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Cognition and RNA Turnover Circuits.  Nonsense-mediated RNA decay (NMD) is a RNA turnover pathway that has captured the imagination of both basic scientists and clinicians.  This highly conserved and selective RNA decay pathway degrades specific RNAs as a means to control diverse biological processes. cell-graphical-abstractFor example, NMD is critical for early embryonic development and thus there is clinical interest in NMD’s possible role in aberrant pregnancies, including miscarriages.  It has been demonstrated that some NMD genes, when mutated, cause intellectual disability, leading to efforts to manipulate NMD to treat neurological diseases.  NMD also degrades mRNAs harboring premature termination codons and thus there is considerable enthusiasm in manipulating NMD to treat diseases caused by nonsense and frameshift mutations.  We have studied all these functions of NMD (e.g., Lou et al. Cell Rep 2014; Shum et al. Cell 2016; Jaffrey & Wilkinson Nature Reviews Neuroscience 2018; Huang et al. Mol Psych 2018; Tan et al. eLIFE 2020).  To understand its role in neural development, we have generated NMD-deficient mouse models, which we are currently studying in detail.  We are also generating and analyzing induced pluripotent stem cells (iPS) cells from human patients with NMD deficiency.

 

                                             

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