March 24, 2021

STRAP regulates alternative splicing fidelity during lineage commitment of mouse embryonic stem cells

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featured discovery

Pran web resizePran Datta, Ph.D.Pran Datta, Ph.D., professor in the Division of Hematology and Oncology, Department of Medicine, is the latest winner of the School of Medicine’s Featured Discovery. This initiative celebrates important research from School of Medicine faculty members.

Datta and his colleagues’ paper, “STRAP regulates alternative splicing fidelity during lineage commitment of mouse embryonic stem cells,” was recently published in Nature Communications.

The team, led by first author Lin Jin, Ph.D., instructor in the Department of Dermatology and formerly research-scientist in Datta’s laboratory, first cloned a gene Strap (that encodes STRAP protein) several years ago and characterized its role in promoting malignant tumors.

“As several deregulated proteins and pathways in cancer are also important for embryonic development, we wanted to understand the non-malignant functions of this protein during development,” Datta says.

They found that eliminating this gene during murine embryogenesis results in a very early lethality; establishing its role in developmental stages.

As part of embryo formation, DNA must be turned into RNA, and then proteins, for cellular functions. Interestingly, RNA can be reorganized to result in many different forms of protein from one DNA sequence. This process is called alternative splicing (AS).

“To date, it was unknown how AS occurs in embryos, but here, we show that STRAP regulates this process in a very specific way. Notably, STRAP regulates this reorganization of RNA in the nervous system during differentiation of embryonic stem cells,” Datta explains.

The investigation, in conjunction with the team’s previous study (Jin et al, Cancer Research, 2017), demonstrates how STRAP is involved in differentiation of embryonic stem cells (ESCs), whereas it promotes stemness of cancer cells.

In addition to Jin as first author on the study and Datta’s work, other collaborators included: Chenbei Cheng, Ph.D., professor in the Department of Cell, Developmental and Integrative Biology; David Crossman, Ph.D., associate professor in the Department of Genetics; Hengbin Wang, Ph.D., associate professor in the Department of Biochemistry and Molecular Genetics; Mariangela Scarduzio, Ph.D., instructor in the Department of Neurology; James Mobley, Ph.D., associate professor in the Department of Anesthesiology; and Malay Basu, Ph.D., assistant professor in the Department of Pathology.

Read the full publication here.

The School of Medicine communications staff sat down with Dr. Datta to gain insights about the research of this study, UAB, and the science community.

Q: What compelled you to pursue this research?

After we cloned STRAP in our laboratory, we observed that its upregulation in colon, lung, and breast cancers promotes tumor initiation, progression and metastasis. In colon cancer patients, upregulation of STRAP associates with worse survival following adjuvant therapy. In contrast, patients carrying tumors with normal or low STRAP expression benefits from the treatment, suggesting essential functions of STRAP in chemoresistance. This is supported by the fact that STRAP promotes cancer cell stemness. In an attempt to study these pro-oncogenic functions of STRAP in vivo, we observed that STRAP knockout mice is embryonic lethal. We, therefore, wanted to understand the mechanism of function of STRAP in embryonic development.

Q: What was your most unexpected finding?

In general, we have two significant discoveries. First, our studies decipher the role of STRAP in modulating splicing programs associated with lineage-specific commitment, alteration of which by STRAP deficiency causes embryonic lethality in mice. Second, in Xenopus, loss of STRAP leads to impeded lineage differentiation in embryos, delayed neural tube closure, and altered exon skipping, indicating conserved evolutionary functions of STRAP.

Q: How do you feel your research will impact the science community?

Specific transcriptional and post-transcriptional events play a vital role during embryonic development. However, in early mammalian embryogenesis, the regulatory mechanisms at the post-transcriptional level for orchestrating germ layer determination and morphogenesis remain largely elusive. Alternative splicing, a post-transcriptional event, results in substantial proteomic expansion and is conserved in a function specific manner across vertebrate species.

Our work reveals that deletion of STRAP has crucial effects mainly on exon skipping during the lineage commitment. STRAP defines a genome-wide alternative splicing network, which establishes a reference dataset for mammals and elucidates the role of STRAP in RNA biogenesis. These studies fill a gap in understanding embryonic organogenesis and the role of STRAP in the cross-regulatory network among RNA binding proteins.

Q: What is your research’s relevance to human disease?

Spinal muscular atrophy (SMA) is a neurodegenerative disease that results from the loss of function of the SMN1 gene, encoding the ubiquitously expressed survival of motor neuron (SMN) protein. It has been reported that STRAP is involved in the intracellular distribution of the survival motor neuron (SMN) complex 1 and regulating the function of this complex. We also found that loss of Strap leads to impeded lineage differentiation and delayed neural tube closure in Xenopus embryos. Therefore, these studies will provide insights into whether STRAP can be targeted for the SMA disease.

Q: When did you know you had an important discovery?

To determine the functional mechanism of STRAP in cancer development and metastasis and in drug resistance, we employed zinc finger nuclease (ZFN) technology to generate Strap knockout mice. When we realized that Strap deficient mice are embryonic lethal, we considered it an important discovery. However, it brought two big challenges: 1) we had to generate conditional knockout mice to finish the cancer studies in vivo; and 2) next we had to investigate the cause of embryonic lethality. In an effort to address the second challenge, we made another discovery that STRAP, by regulating alternate splicing network, is required for mouse early embryo development and differentiation of embryonic stem cells.

Q: What do you find makes the science community here unique?

The science community with diverse expertise at UAB is highly collaborative and resourceful. A wide variety of interdisciplinary researchers in the UAB O’Neal Comprehensive Cancer Center and at UAB are available for high quality basic, translational and clinical research. These are extremely important for increasing the success of the research community.