RESEARCH

Regulation of gene expression during germline stem cell self-renewal and differentiation

Germ cells are considered to be the ultimate stem cell lineage because they have the ability to generate more germ cells as well as give rise to a new organism for every generation. Not surprising, the study of the germline has been instrumental for the understanding of the mechanisms of pluripotency and stem cell biology, with broad implications to regenerative medicine, aging, and cancer. Recently, we assembled the complete genetic framework controlling germline stem cell self-renewal and differentiation in vivo (Sanchez et al, 2016). This was accomplished by performing an unbiased, transcriptome-wide in vivo RNAi

screen, followed by in-depth developmental,

genetic, and computational analyses. Further

analysis led us to discover exciting new aspects

of germline development, including the translational

control of stem cell cytokinesis, the uncoupling of

ribosome biogenesis and protein synthesis rates

during stem cell development, and an energy

metabolism-independent function for mitochondria

governing differentiation

(Teixeira et al, 2015; Sanchez et al, 2016).

From plants to mammals, accumulated evidence indicate that regulation of protein synthesis plays critical roles during organism development, tissue homeostasis, and tumorigenesis (Teixeira & Lehmann, 2019). However, the study of spatiotemporal regulation of gene expression and its function in controlling stem cell biology has been mostly restricted to chromatin-based mechanisms. Interestingly, translational regulation appears prominent in the germline, as no master transcription factor has been identified to specify germ cell fate. Indeed, our unbiased RNAi screen identified many translation regulators as being critically required for defined aspects of germline stem cell development. Using a combination of high-throughput molecular approaches, computational investigation, as well as developmental and genetic analyses, we are dissecting the molecular mechanisms by which protein synthesis control - a new frontier in gene regulation - govern key aspects of germline stem cell development in vivo (Gui & Teixeira, 2021).

Transposable elements and genome stability

A large fraction of our genome (up to 50%) consists of selfish DNA modules known as transposable elements (TEs) – mobile units that aim to increase in copy number by jumping from one location to the other. Since their discovery, transposable elements have been involved in the organization, functioning, and evolution of genomes, but their uncontrolled activity is detrimental to the host and

must therefore be tightly regulated. This is especially true in the germline, the battleground where host and transposon mechanisms compete for

maximizing their influence over the genetic

information that will be passed to the following

generations. On one side, selfish elements aim to

increase in copy number by mobilization, while on

the other side host mechanisms act to suppress TE

activity and its detrimental effects. Often balanced,

these two opposed actions are thought to safeguard

the functional and structural integrity of the genome

while allowing genome evolution (Gebert et al, 2021).

 

A classic example of disruptive transposon activity is provided by hybrid dysgenesis in Drosophila, a syndrome that specifically affects germline development and is triggered by the P-element DNA transposon (Malone et al, 2015). In this system, the presence of epigenetically inherited small RNAs (sRNAs) cognate to the P-element correlates with germline protection.  Unexpectedly, we found that such sRNAs regulate P-element splicing during hybrid dysgenesis, leading to the accumulation of inactive transcripts in Drosophila germ cells (Teixeira et al, 2017). Using this textbook example of genomic conflict and transgenerational epigenetics, we use a combination of developmental and high-throughput molecular approaches to dissect the host mechanisms controlling genome stability and transposon activity during germline development.