You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.

Title: GRHL3 binding and enhancers rearrange as epidermal keratinocytes transition between functional states}
Article:
Abstract:
Transcription factor binding, chromatin modifications and large scale chromatin re-organization underlie progressive, irreversible cell lineage commitments and differentiation. We know little, however, about chromatin changes as cells enter transient, reversible states such as migration. Here we demonstrate that when human progenitor keratinocytes either differentiate or migrate they form complements of typical enhancers and super-enhancers that are unique for each state. Unique super-enhancers for each cellular state link to gene expression that confers functions associated with the respective cell state. These super-enhancers are also enriched for skin disease sequence variants. GRHL3, a transcription factor that promotes both differentiation and migration, binds preferentially to super-enhancers in differentiating keratinocytes, while during migration, it binds preferentially to promoters along with REST, repressing the expression of migration inhibitors. Key epidermal differentiation transcription factor genes, including GRHL3, are located within super-enhancers, and many of these transcription factors in turn bind to and regulate super-enhancers. Furthermore, GRHL3 represses the formation of a number of progenitor and non-keratinocyte super-enhancers in differentiating keratinocytes. Hence, chromatin relocates GRHL3 binding and enhancers to regulate both the irreversible commitment of progenitor keratinocytes to differentiation and their reversible transition to migration.
Introduction:
Gene expression changes in stem cells committing to cellular lineages correspond to large scale reorganization of epigenetic regulatory structures, including super-enhancers( SEs)[1–4], which are thought to be more important than typical enhancers( TEs) in controlling cell identity[1, 5–7]. Less is known about the chromatin regulatory changes corresponding to transitions of committed cell types to reversible functional states, including migration. Here we used primary human epidermal keratinocytes[8–12] to investigate the genomic regulatory structures underpinning different functional states of a committed cell type. As epidermal progenitors in the basal layer exit the cell cycle, they move towards the surface of the skin, progressively differentiating by activating gene expression programs required for epidermal barrier formation[13]. During early wound healing, however, these progenitors migrate to cover the wound, activating a gene expression program distinct from that of differentiation[14]. While both migration and differentiation require distinct gene expression changes, chromatin changes in transient functional states such as migration remain uncharacterized. Essential for embryonic epidermal differentiation and barrier formation, and adult epidermal repair, the transcription factor Grainyhead-like 3( GRHL3; also referred to as GET1) activates gene expression programs required for cell adhesion, lipid production, cornified envelope formation and protein crosslinking[15–17]. Intriguingly, GRHL3 is also essential for normal keratinocyte migration during eyelid closure and wound healing[18–20] where it modulates gene expression programs that promote the movement of keratinocytes and suppress the progenitor and differentiation states. How a single transcription factor GRHL3 can promote both differentiation and migration of a single cell type remains poorly understood. The formation of unique complements of enhancers, genomic regulatory regions residing at a distance from their target promoters, is critical for cell type specifications. Initially discovered as short regions that activate transcription independent of orientation or location relative to target promoters[21], enhancers are now known to be bound by active transcription factors[22]. More recently, advances in DNA sequencing enabled the identification of gene regulatory regions based on histone modifications. High levels of H3K4me1 and low levels of H3K4me3 mark enhancers; during enhancer activation, high levels of H3K27ac are also found[23, 24]. Poised enhancers, so named because they are repressed while primed for rapid activation, have both H3K4me1 and the repressive mark H3K27me3[23]. Recent work classified enhancers into TEs( usually about 1–2 kb long) and SEs that are longer( greater than 12. 5kb) with higher intensity of cooperatively binding transcription factors and higher H3K27Ac activation marks[1]. By driving the expression of cell identity genes, SEs are more important for cell type specifications than TEs[1, 4, 6]. Whereas recent studies mapped SEs in human epidermal keratinocytes during differentiation and showed that transcription factor p63[2] and DNA methylation enzymes DNMT3A and DNMT3B[25] bind and regulate their activity, the regulatory role of SEs for reversible functional states like migration remains unexplored. Also, we don’t know if transcription factors such as GRHL3 regulate the formation of TEs and SEs in epidermal keratinocytes. To address the aforementioned knowledge gaps, we defined the TE and SE complements in progenitor, migrating, and differentiating keratinocytes. Combining this data with gene expression data after siRNA knockdowns of 50 epidermal differentiation-associated transcription factors, we gained a high-level view of the transcriptional regulation of transitions between different epidermal functional states. A focus on one of these transcription factors, GRHL3, provides mechanistic insight into how a single transcription factor can control distinct gene expression programs under different physiological states within the same cell type. Our studies suggest that GRHL3 regulates divergent gene expression programs in differentiating and migrating keratinocytes by switching locations of chromatin binding in the context of enhancer landscapes that are distinct for each state.
Discussion:
Compared to TEs, SEs are more directly linked to gene expression that confers cell type specification[1, 6]. In ESCs, where SEs have been most extensively studied, the genes encoding pluripotency factors are linked to SEs and binding sites for the pluripotency factors themselves are also enriched in SEs[1]. Analogous observations were made for the relationship between SEs and cell type specifying transcription factors in differentiated cells[4, 46, 47], and between SEs and oncogenes in transformed cells[48]. These findings, and the fact that common disease SNPs are overrepresented in SEs[6], point to SEs’ important regulatory functions. Our findings suggest that in addition to controlling cell type specification, SEs control migration, a transient functional state of lineage committed cells-- while a core group of SEs remains unchanged, keratinocytes activate unique subsets of SEs as they transition from progenitors to either differentiation or migration. The SEs identified here have features previously described in other cell types, including the enrichment of disease-associated SNPs and higher expression of SE-associated genes than TE-associated genes. We have also identified new features of SEs in keratinocytes. First, in contrast to TEs, which frequently arise in the keratinocyte lineage from unmarked chromatin regions in ESCs, the majority of SEs in progenitor keratinocytes derive from chromatin regions already marked by H3K4me1 in ESCs, suggesting that SEs arise in more stable regulatory regions already marked for regulatory potential early in development. Second, GRHL3 knockdown leads to the appearance of novel SEs in differentiated keratinocytes, suggesting that GRHL3 represses non-keratinocyte SEs. A number of the new SEs formed after GRHL3 knockdown are linked to neuronal gene expression, indicating that cell-type specific transcription factors can act to repress the formation of spurious SEs normally active in related cellular lineages. Interestingly, Polycomb factor CBX4 also represses neuronal cell gene expression in the epidermis[49], raising the possibility that GRHL3 could recruit the chromatin-modifying CBX4 to repress the formation of non-keratinocyte enhancers. Third, we found that keratinocyte SEs have propensity to locate at the edges of important epidermal gene clusters, including that of the EDC and keratin clusters, suggesting that SEs may promote loops between boundary enhancers and the promoters of genes within the cluster. In fact, locus control regions were some of the earliest identified enhancers and more recently have been shown to overlap SEs[6]. Our siRNA dataset provides a wealth of information about transcriptional regulation during the transition from progenitor to differentiated keratinocytes. By combining chromatin landscape features with this functional gene expression data, we identified a set of “hub” transcription factors, including ETS1, SMAD4, RUNX2, and PRDM1, that are close to SEs and whose motifs are enriched within many of the SEs linked to other epidermal transcription factor genes. Each of these factors shows a distinct pattern of association with the temporal gene signatures of epidermal differentiation. For example, PRDM1 shows little correlation with the progenitor signature, but an increasingly positive correlation across early, mid, and late differentiation. Other factors are primarily linked to progenitor and early gene expression, including FOSL1, CREB5, and STAT1. Our findings suggest that “hub” transcription factors may bind to and regulate SEs at specific time points during differentiation, ensuring the correct sequence of events for a successful transition from a progenitor to a differentiating cell. Interestingly, we find that two SNPs linked to skin diseases overlap the ETS1 gene, although both fall outside of the ETS1-linked SE. Since ETS1 is one of the “hub” transcription factors identified by the network analysis as acting early in differentiation to regulate other epidermal transcriptional regulators, even mild disruption of ETS1 expression or function could have pathological downstream effects on epidermal differentiation in diseases like psoriasis[17]. The data also show several examples where different members of transcription factor families, including the AP1, GRHL, OVOL, and SOX families, affect distinct stages of epidermal differentiation, which is consistent with the distinct epidermal phenotypes when the genes encoding different family members are deleted in mice[15, 26, 50–52]. Our data on dual roles of GRHL3 in the transitions from progenitors to migration or differentiation increase our understanding of how a single transcription factor can perform unique regulatory functions in two cell states. The GRHL3-REST[53] co-regulation in migrating keratinocytes is a novel finding, and while targets of REST have been shown to have a role in keratinocyte migration[45], our study is the first to identify a direct regulatory role for REST in keratinocyte migration and to identify shared REST and GRHL3 gene targets. We were unable to detect a direct interaction between REST and GRHL3, suggesting that the GRHL3-REST interaction is chromatin dependent. Many of the shared targets of REST and GRHL3, the majority of which are repressed by the two factors, are inhibitors of cell migration and of axon projection in neurons. Consistent with our finding for GRHL3 and REST in repressing inhibitors of migration, including genes regulating cell projections, GRHL3 has been shown to act in leading edge cells during migration, promoting actin polymerization and filopodia projections[19]. In sum, GRHL3 and REST regulate a group of shared genes involved in neuronal and keratinocyte migration and development.
The epidermis , a continuously renewing epithelium , balances proliferation and differentiation during development and homeostasis . During wound healing epidermal keratinocytes become migratory to close the wound . The transition of keratinocytes between these three different states—progenitor , differentiation and migration-requires the activation of distinct gene expression programs whose regulation is poorly understood . Our study demonstrates how regulatory chromatin domains like typical enhancers and super enhancers interact with transcription factors , resulting in complex layers of regulation with specific transcription factors regulating distinct stages of the epidermal differentiation process . Specifically , the epidermal transcription factor GRHL3 regulates both possible transitions of progenitor epidermal cell: differentiation and migration . We found that both GRHL3 chromatin binding and enhancers relocate as keratinocytes move between functional states . In addition , we show reciprocal regulation between GRHL3 and enhancers: chromatin domains , including a super enhancer , regulate GRHL3 expression , while GRHL3 regulates the formation of a subset of epidermal super enhancers and typical enhancers .