Transcriptional control of stem cell fate by E2Fs and pocket proteins

Abstract

E2F transcription factors and their regulatory partners, the pocket proteins (PPs), have emerged as essential regulators of stem cell fate control in a number of lineages. In mammals, this role extends from both pluripotent stem cells to those encompassing all embryonic germ layers, as well as extra-embryonic lineages. E2F/PP-mediated regulation of stem cell decisions is highly evolutionarily conserved, and is likely a pivotal biological mechanism underlying stem cell homeostasis. This has immense implications for organismal development, tissue maintenance, and regeneration. In this article, we discuss the roles of E2F factors and PPs in stem cell populations, focusing on mammalian systems. We discuss emerging findings that position the E2F and PP families as widespread and dynamic epigenetic regulators of cell fate decisions. Additionally, we focus on the ever expanding landscape of E2F/PP target genes, and explore the possibility that E2Fs are not simply regulators of general 'multi-purpose' cell fate genes but can execute tissue- and cell type-specific gene regulatory programs.

Keywords: E2F transcription factors; cell cycle; epigenetics; neural precursor cell (NPC); pocket proteins; stem cell fate; stem cells; transcription.

FIGURE 1

E2Fs/PPs control diverse classes of cell fate regulatory processes and associated genes. Transcriptional regulation of non-classical, cell cycle-independent, genes by E2Fs and PPs has been associated with a number of biological processes that impact stem cell fate. These processes include: quiescence, proliferation, metabolism, differentiation and lineage choice, cell death and survival, migration of newly committed cells, stem cell self-renewal, and cellular reprogramming (specifically, reprogramming of fibroblasts to pluripotent SCs). Where examples are known, select cell fate-associated genes that have been confirmed as functional targets of E2Fs/PPs are indicated in red italicized font. References for cell death/survival genes are as follows: (Irwin et al., 2000; Moroni et al., 2001; Hershko and Ginsberg, 2004; Tracy et al., 2007). See the main text or Table 1 for additional references.

FIGURE 2

E2Fs and PPs regulate cell fate in diverse stem cell populations. Here, we highlight examples of mammalian stem cell (SC) populations in which biological roles for E2Fs and/or PPs in cell fate regulation, outside of classical cell cycle control, have been documented. These cell types include SC populations representing all three embryonic germ layers (ectoderm, mesoderm, endoderm), as well as pluripotent SCs (in ESCs as well as during cellular reprogramming to iPSCs), germ (spermatogonial) SCs, and extra-embryonic trophoblasts. We indicate the E2F and PP factors that have been implicated in cell fate regulation in each SC type. See the main text or Table 1 for references.

FIGURE 3

Tissue-specific gene regulation by E2F3. Genome-wide analyses in precursors of skeletal muscle and neurons have revealed the existence of tissue-specific target genes, as well as genes that are likely to be constitutively regulated in most tissues. Constitutive and tissue-specific E2f3 targets are enriched in different functional categories (gene ontologies), with cell cycle-related functions being most represented by constitutive targets of E2f3. Additionally, gene promoter sequence analyses suggest that E2f3 may cooperate with different transcriptional regulators, depending on the cell type: with Nrf1 (Cam et al., 2004), Sp1 (Blais et al., 2002), and NF-y (Caretti et al., 2003; Elkon et al., 2003; Zhu et al., 2004) for constitutive cell cycle target genes, with Ctcf in neural precursors (Julian et al., 2015) and with MyoD and Runx in myoblasts [unpublished analyses performed using Whole Genome rVista (Dubchak et al., 2013)].