# Mechanisms of gene regulation mediated by human-specific SVA transposons

> **NIH NIH R35** · THOMAS JEFFERSON UNIVERSITY · 2022 · $65,000

## Abstract

Summary
Transposable Elements (TEs) account for ~50% of the human genome, and several lines of evidence now
suggest an extensive role for these parasitic elements as a critical source of gene-regulatory novelty in mammals.
In this context, my laboratory aims at unveiling the mechanisms that TEs adopt to regulate and rewire mammalian
gene regulatory networks. In particular, the fundamental problem that we aim to solve is how a very recent
genomic invasion by young mobile elements (SINE-VNTR-Alus = SVAs) has set the ground for human-specific
traits. Among the 5 main TE classes, SVAs are the youngest, and include 7 subfamilies being either hominid-
specific (SVA-A, -B, -C, and -D) or human-specific (SVA-E, -F, and F1). Importantly, SVAs are still replication
competent in humans, and over 60% of the existing human SVA copies are located within 10 kb of a coding
gene. Given their young age, SVAs are particularly relevant for understanding human evolution. Our preliminary
data show that genes proximal to human-specific SVA insertions are enriched for biological processes
associated with brain development, craniofacial morphology, and cognitive behavior. Moreover, SVAs are
among the most epigenetically de-repressed and transcriptionally upregulated TEs across a multitude of
cancers. Our recent work demonstrated that the large majority of human-specific enhancers and promoters
contain SVA insertions, and that SVA transposition within enhancer bodies correlates with either increased or
decreased associated gene expression, with well-defined tissue-specific patterns. In spite of the conspicuous
lines of evidence suggesting that SVAs are important regulators of human gene expression, we still have limited
knowledge of the biology of these TEs. For example, we do not know the mechanism by which SVAs enhance
AND repress transcriptional activity on host genes, tissues-specifically. We do not know which component(s) of
the modular structure of these TEs drives the regulatory activity. Finally, and more importantly, we do not know
the relative contribution of human-specific SVAs to the rewiring of human-specific regulatory networks, and to
the generation of human specific traits. To fill these gaps of knowledge, we will apply our genomic expertise to
human and chimpanzee's induced Pluripotent Stem Cell differentiation, using hippocampal neurogenesis as a
proof of principle. Moreover, to address the mechanism, we will harness human cell-lines, CRISPR/Cas9, and
genomics. We will deconstruct the complex modular architecture of SVAs, and define the mechanism adopted
by SVAs to drive regulatory activity on the host genome. We will delve into the tissue-specific repressive activity
displayed by select SVAs to uncover the underlying mechanism, also testing the hypothesis that a subset of
SVAs offers a genome-wide substrate for a critical transcriptional repressor (YY1). With the proposed research
we will gain transformative insights on how human-specific traits are gen...

## Key facts

- **NIH application ID:** 10442447
- **Project number:** 5R35GM138344-03
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Marco Trizzino
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $65,000
- **Award type:** 5
- **Project period:** 2020-07-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10442447

## Citation

> US National Institutes of Health, RePORTER application 10442447, Mechanisms of gene regulation mediated by human-specific SVA transposons (5R35GM138344-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10442447. Licensed CC0.

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