The overarching goal of research in the Batista Lab is to understand the role of telomere dysfunction in human disease, cancer and aging. Our laboratory uses genome-wide methods to uncover alterations that drive cellular failure upon progressive telomere dysfunction, using human pluripotent cells (including both embryonic and induced pluripotent stem cells) as a primary model. We combine in vitro biochemical and mechanistic studies with our ability to generate and differentiate human pluripotent stem cells to better understand the importance of telomere maintenance in humans and to determine the events that lead from telomere shortening to disease in humans.
Cellular reprogramming and engineering
The study of disease-associated, genetic mutations in telomerase is complicated by low expression of specific telomerase components in human cells. Additionally, different biochemical properties between human and mice telomerase make the study of patient mutations hard to perform in mice models. To overcome these limitations our lab uses cellular reprogramming from patient fibroblasts with different mutations in telomerase, coupled with genome engineering by CRISPR/Cas9 to create novel, physiologically relevant human ES and iPS cells to study the consequences of telomere dysfunction in cellular and tissue development.
Telomerase dysfunction during blood cell development
Dyskeratosis congenita (DC) is a bone marrow failure syndrome associated with telomere dysfunction. The progression and molecular determinants of hematopoietic failure in DC remain poorly understood. In collaboration with Chris Sturgeon’s lab at Washington University, we directly differentiate human embryonic stem cells harboring mutations in telomerase to understand the consequences of DC-associated mutations on the primitive and definitive hematopoietic programs. We established hematopoietic failure in DC is restricted to the definitive program and it is caused by DNA damage accrual and is mediated by p53 stabilization. With this model we have created a unique and extremely robust platform for therapeutic discovery for treatment of DC patients. We are currently pursuing different molecular strategies to achieve this goal, partnered with other collaborators, including Roy Parker’s lab at HHMI/UC Bolder.
Hepatocyte development in settings of accrued DNA damage
Hepatocellular carcinoma (HCC) is the fifth most common human cancer. More than 80% of HCCs develop from the formation of fibrotic tissue in the liver. It is well established that hepatocytes play a central role in this response. Interestingly, patients with loss-of-function mutations in telomerase are at an increased risk of developing this condition. However, due to lack of adequate models, the role of telomerase and telomere dysfunction has not been rigorously studied in human disease. To circumvent this, we have recently created novel cellular models that allow the identification of the precise mechanisms behind hepatocyte in settings of telomere erosion and accrued DNA damage.
Metabolism and telomere shortening in aged cells
Stem cell dysfunction plays a key role in loss of tissue homeostasis during aging. Telomere maintenance and mitochondria activity are important factors contributing for long-term stem cell integrity and function. However, it is unclear if these processes are molecularly linked. We are exploring molecular links between telomere shortening, mitochondria alterations and human stem cell exhaustion. Using genome editing techniques coupled to high-throughput gene expression analysis, electron microscopy and extracellular flux assays, we are currently addressing if there is a particular telomere length that promotes mitochondria impairment and, more importantly, to which extent telomere re-elongation can rescue human stem mitochondria and stem cell function in telomere-aged populations.