The Role of HERVH-derived transcripts in non-pluripotency associated processes
PhD student Aleksandra Kondrashkina
Transposable Elements (TEs) are best described as molecular parasites with the potential to give rise to a variety of genetic alterations. Such alterations include mutational damage to gene function, but can also provide useful genetic variability in host genomes. Thus, in contrast to most viruses, transposable elements and host have coevolved in a way that permits propagation of the transposon, but minimizes damage to the host. TEs make several interactions to host cellular machineries, piggyback and modify certain basic mechanisms of the host organism.
HERVH is a primate-specific endogenous retrovirus, which was domesticated during the last 10 million years. HERVH-derived transcripts have been implicated to be incorporated into the regulatory network of primate/human pluripotency. The goal of the project is to elaborate the roles of HERVH transcripts during human preimplantation embryogenesis.
Transposon-host interactions as a model to investigate stress signaling and response in human cells
Dr. Suneel Narayanvari
TEs are often envisioned as stress-responsive “genomic noise-generators”. Our earlier studies clearly indicate that Sleeping Beauty (SB) transposition is sensitive to stress and stress signaling, and its response to these signals involves a complex, interactive regulatory platform involving evolutionary conserved cellular mechanisms. To model how a vertebrate-specific transposon senses and responds to stress signals in human cells, we study molecular interactions of a transposon with host cellular mechanisms to understand how stress-signaling and response triggers transposon activation. This experimental setup mimics a situation of a new TE colonizing a naïve Genome.
Transposition and cell cycle
Dr. Suneel Narayanavari, Andrea Smith*
A temporary arrest at the G1/S transition phase of the cell-cycle was found to enhance transposition, suggesting that SB transposition is favored in the G1 phase of the cell-cycle, where the NHEJ pathway of DNA repair is preferentially active (Izsvak, 2004; Walisko, 2006). Recent findings indicate that, in addition to G1/S arrest, a temporal arrest in G2/M might also induce transposition. Notably, in contrast to certain viruses, severe DNA damage (e. g. DSBs) does not seem to trigger SB transposition, reflecting different strategies of various parasites that piggyback cellular processes.
Repairing transposition-inflicted DNA lesions
Yongming Wang*, Ilija Bilic*, Helena Escobar*, Dr. Suneel Narayanavari
Cellular mechanisms that are directly involved in repairing transposition-inflicted DNA lesions or can attenuate the damage should have crucial role in establishing stable host-transposon co-existence. TEs can transpose by replicative or non-replicative processes. Non-replicative “cut & paste” type transposons, such as SB, excise from one genomic locus and insert into another. This model, however, does not provide explanations for the significant copy numbers these elements can reach in genomes (~3% in the human genome). Thus, how cut & paste transposons were amplified and propagated in vertebrate genomes is not yet clear. In principle, a transposon can take advantage of the cellular repair machinery to amplify its own genome. These studies will help us to understand how TEs similar to SB amplified in the human genome, and what factors influenced this process.
Transposed Elements aid embryonic development
Transposable or Transposed elements (TrEs) are a productive source of biochemically active non-coding or occasionally coding elements that are tightly regulated in a cell-type specific manner. Many recent studies strengthen the hypothesis that few of these elements are co-opted for the regulation of host genes. We focus on one particular large family of human ERVs, which we find as a key regulatory player in the human pluripotent stem cells. I show that its co-option has potentially led the evolution and development of human-specific embryogenesis including the pluripotency. We updated transcriptomic encyclopedia of early human embryogenesis with their transcriptional flags. We re-define the progression of human embryogenesis at single-cell resolution with their markers. In conjecture with previous definitions, we characterize an unattended cell population in human preimplantation embryos that did or did not commit to any of the known lineages in order to form the stable blastocyst. Human transposcriptomics illustrate the contrasting pattern of transposon families during the progression of preimplantation embryogenesis. Their cross-talk with host factors could have driven the commitment of host cells to the particular lineages, leading to rapid turnover, compared with another species.
Functional significance of Sleeping Beauty transposase – HMGXB4 interaction
PhD student Guo Young
In our previous studies, we identified HMG2l1/HMGXB4 as an interactor of the Sleeping Beauty transposase. Phylogenetic tree analysis shows HMGXB4 is a conserved gene from fish to human. In our follow up studies, we are trying to decipher the potential functions of HMGXB4, which may help us to understand the functional significance of such interaction between Sleeping Beauty transposase and its interacting Partner.
HMGXB4 targets transposition
Anantharam Devaraj* and Manvendra Singh
We have shown earlier that HMGXB4/HMG2l1 (a component of the Wnt-signalling pathway) is able to physically associate with either the transposon DNA or the transposase protein, providing a negative feedback loop regulation to transposase expression (Walisko, 2008). New data suggest that HMXB4 has a high expression level in undifferentiated cells, but its expression level is dropping in differentiated cells in various models. We propose to validate the working hypothesis that HMGXB4 targets transposition to a well-defined developmental phase. The regulation of SB transposition in association with Wnt-signaling could be fundamentally different from LINE-1 (retrotransposon) regulation that is regulated primarily epigenetically in the human genome. The expression of HMGXB4 is conserved throughout the early development of human, rodents and flies. Which might explain the higher activity of TEs in the germ cells across the phylotree.