Transposable elements in the keratinocyte genome and their regulation during skin development and epidermal differentiation

PROJECT SUMMARY
In addition to signaling/transcription factor-dependent regulatory mechanisms, lineage-specific gene
expression programs in stem cells and their progenies are also regulated epigenetically, i.e., via regulation of
covalent DNA/histone modifications and higher-order chromatin remodeling. Epigenetic regulatory machinery
maintain the progenitor population and epithelial identity in epidermal keratinocytes, as well as inhibit premature
activation of terminal differentiation-associated genes and balance their transcription in differentiating cells.
Transposable elements (TEs) constitute a large portion (44%-55%) of the entire mouse or human
genomes. Most TEs are transcriptionally inactive under physiological conditions, while their inappropriate
activation has been implicated in pathogenesis of autoimmune disorders and carcinogenesis. In keratinocytes,
UV exposure activates transcription of various endogenous retroviral sequences which are closely related to the
sequences activated in lupus erythematosus patients. Furthermore, increasing evidence of data suggest an
involvement of endogenous TEs in the development of pro-inflammatory skin conditions, such as psoriasis.
However, there is a number of critical questions that this project seeks to investigate, remain unclear:
1) Which TEs are expressed in normal keratinocytes during skin development, postnatal homeostasis and
terminal differentiation, 2) Which mechanisms regulate TE silencing in keratinocytes, and 3) When TE silencing
is compromised, how are keratinocyte differentiation and epidermal inflammatory response impacted?
In this Multi-PI proposal, we will address the hypothesis that distinct classes of TEs differentially contribute
to the control of gene expression in epidermal keratinocytes, mediated by epigenetic regulators Lsh and Setdb1
that serve as critical determinants mediating the TE silencing and preventing pro-inflammatory responses in the
epidermis. This hypothesis will be addressed via three Specific Aims:
Aim 1. Define the landscape of transposable element expression in normal mouse and human
keratinocytes during skin development, postnatal homeostasis and terminal differentiation.
Aim 2. Define the roles for Lsh and Setdb1 in the control of transposable element silencing in
keratinocytes.
Aim 3. Define the impact and mechanisms associated with the transposable element activation in
keratinocytes on epidermal inflammatory response.
The generated outputs from this application will provide novel insights into fundamental mechanisms
underlying keratinocyte differentiation in normal mouse and human skin, as well as will promote the development
of novel paradigms for management of disorders of epidermal differentiation and inflammatory responses in
humans via modulation of TE activities.

Grant Number: 5R01AR078306-05
NIH Institute/Center: NIH
Principal Investigator: VLADIMIR BOTCHKAREV