# Evolution of new regulatory networks via genetic arms races between KRAB zinc finger proteins and retrotransposons

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA SANTA CRUZ · 2020 · $685,382

## Abstract

Project Summary / Abstract
This proposal investigates how co-evolution of retrotransposon elements (RTEs) and KRAB zinc finger
proteins (KZNFs) have resulted in new gene regulatory modules and how these modules contribute to
human embryonic development and pluripotency. KZNFs are the largest family of human transcription
factors and have undergone rapid evolution in primates to repress RTE expression. Both RTEs and KZNFs are
highly expressed in pluripotent stem cells (PSCs) and are aberrantly expressed in cancers and neurological
diseases, suggesting that they play functional roles in these cell types. KZNFs show strong signals of selection
and activity even after their target RTEs have lost the ability to mobilize (i.e. generate new insertion events)
and therefore no longer pose a threat to their host genome. We hypothesize that over evolutionary time
KZNFs are maintained by the host to regulate host gene expression after their job repressing RTEs is
finished, and hence tracing the evolution of KZNF-RTE and KZNF-enhancer interactions will not only
increase our understanding of the rules governing ZNF-DNA binding, but open a new window on the
evolution of and mechanisms in primate/human gene regulatory networks. We will use comparative
genomics approaches that take advantage of new, highly contiguous, primate genome assemblies to trace this
evolutionary history. This analysis will allow us to apply assays we have developed to dissect the role of
evolutionary changes to both KZNFs and their RTE/host targets in controlling transcription in PSCs, and by
analogy, in early embryonic cell types.
We will focus our experimental analysis on “naive” and “primed” PSCs, which mimic epiblast cells of pre- and
post-implantation embryos, respectively. These cell types show high expression of a number of specific RTEs
and KZNFs, and these expression signatures differ between closely related species, including between human
and non-human apes. Naive and primed PSCs are experimentally tractable and critical for regenerative
medicine efforts. We have succeeded in making them in human, chimpanzee and orangutan. We will test the
function of KZNF-RTE interactions active in these ape PSCs by modulating both KZNF and RTE
expression and will assess the consequences of these manipulations on cell fate specification,
maintenance of pluripotency and differentiation potential. By performing these experiments in non-human
ape PSCs in addition to human PSCs we can identify conserved and species-specific regulatory programs and
dissect the molecular and evolutionary basis for recently evolved differences in pluripotency in humans.
The results of this work will reveal how RTEs and KZNFs have influenced human evolution and development
and provide important insights into the establishment and maintenance of pluripotent stem cells.
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## Key facts

- **NIH application ID:** 9872195
- **Project number:** 5R01HG010329-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA CRUZ
- **Principal Investigator:** Sofie Reda Salama
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $685,382
- **Award type:** 5
- **Project period:** 2019-02-12 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9872195

## Citation

> US National Institutes of Health, RePORTER application 9872195, Evolution of new regulatory networks via genetic arms races between KRAB zinc finger proteins and retrotransposons (5R01HG010329-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9872195. Licensed CC0.

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