The control of gene expression plays a critical role in development and cell differentiation while incorrect gene expression patterns lead to many diseases including cancer. Transcription factors and enhancers work together during development to produce distinct gene expression patterns that vary across different cell lineages and developmental stages.
Studying enhancers provides crucial insights into gene regulation which helps both to understand developmental processes and to target disease treatment. TCF-1 represents an HMG-box transcription factor produced by the T-cell Factor 7 (TCF7) gene with critical functions in developmental processes and bodily equilibrium. TCF-1 functions as an essential transcription factor during the initial development phases of T cells and innate lymphoid cells (ILCs). Scientists have yet to determine how TCF-1 expression is regulated.
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Introduction to T-cell Factor 7 (TCF7)
T-cell Factor 7 (TCF7) represents a transcription factor within the TCF/LEF protein family. TCF7 regulates multiple physiological functions which include cell fate determination and development as well as immune response and tumor development. This section provides an abbreviated description of TCF7's structural composition and physiological functions.
Structure
TCF7 protein contains some important domains, HMG (High Mobility Group) domain: TCF7 binds to DNA through this domain which commonly connects with the Wnt signaling pathway. The transcriptional activation function of TCF7's C-terminus allows it to bind with other transcription factors to drive target gene expression. Protein β-catenin interacts with TCF7 through homodimer formation to perform its function. The binding process represents an essential stage for initiating the Wnt signaling pathway.
Physiological Activity
TCF7 serves as a central component within the Wnt signaling pathway. The stabilization and nuclear transfer of β-catenin occurs after its binding to the cell membrane receptor by the Wnt ligand which enables it to bind with TCF7 and activate downstream target genes. TCF7 takes part in multiple physiological processes during embryogenesis including germ layer formation together with organ development and stem cell maintenance. TCF7 plays a critical function in T cell development and operation by managing their differentiation while maintaining their proliferation and survival capacity. TCF7 functions to regulate both immune responses and the determination of cell fate. TCF7 contributes significantly to stem cell self-renewal and differentiation within tissues that experience rapid renewal like the intestine and skin.
TCF7 Involved in Important Physiological Activities
TCF7 belongs to the T cell factor family which includes TCF7 an essential part of the core regulatory network that maintains the pluripotency-differentiation equilibrium in mouse embryonic stem cells. EML cells express Tcf3 at very low levels while other TCF family members alongside TCF7 failed to demonstrate the substantial gene expression differences seen with TCF7. Other interesting transcription factors that we found to be upregulated in CD34+ cells include: The transcription factors Sox4, Jun, Stat3, Smad1, Cebpa, Bcl6, Bcl3, Bcl9, Fos, Runx1, and Cbfb show increased expression in CD34+ cells.
TCF7 Functions as a Crucial Regulatory Element for Multipotent Hematopoietic Cells
In a self-contained process EML cells produce both self-renewing Lin-SCA+CD34+ cells and non-renewing differentiated Lin-SCA-CD34- cells. The HMG box protein TCF7 operates as a control point for the self-renewal/differentiation transition without autocrine Wnt signaling. Tcf7 showed the highest level of downregulation as transcription factor during the transition of CD34+ cells to CD34- cells. Researchers used ChIP-Seq to identify the target genes bound by TCF7. TCF7 interacted with the promoter regions of RUNX1 (AML1) and RUNX1 generated its short isoform with TCF7's presence while the long isoform did not require TCF7 indicating a specific regulatory synergy between TCF7 and the short RUNX1 isoform. Experiments that reduced TCF7 levels and gene set enrichment analysis demonstrated TCF7's dual function in activating genes typical of self-renewing CD34+ cells and suppressing genes active during partial differentiation of CD34− cells.
Fig 1. RUNX1 and TCF7 work together to regulate target genes (Wu, J., et al. 2012).
TCF7 Cytokine Controls Osteocalcin Signaling
Osteocalcin maintains energy balance by activating several biological pathways. As a primary organ for energy metabolism, adipose tissue interacts with recombinant osteocalcin administration in mice to increase energy usage which helps fight obesity and glucose intolerance. The activation of Gprc6a gene expression occurs through brown fat-like differentiation which encodes a G protein-coupled receptor functioning as an osteocalcin receptor. Osteocalcin boosts Gprc6a expression beyond its initial activation. The significance of Gprc6a in the activation of thermogenic genes by osteocalcin was confirmed through both overexpression and knockdown experiments. Osteocalcin signaling potentially targets Tcf7 and Wnt3a. TCF7 is part of the TCF/LEF1 DNA-binding factor family and plays an essential role in the canonical WNT/β-catenin pathway but activates Gprc6a and Ucp1 promoters through a mechanism that does not involve β-catenin. Research has demonstrated that TCF7 activity depends on both the thermogenic coactivator PRDM16 and the histone demethylase LSD1.
The Factor TCF7 Participates in the Developmental Process of Both Early T Cells and Innate Lymphoid Cells
TCF-1 which TCF7 encodes holds a vital function across multiple hematopoietic cell lineages. The molecular regulation of TCF7 occurs in T cells as well as innate lymphoid cells and migratory conventional dendritic cells. The initiation of TCF7 expression in T cells and innate lymphoid cells requires a specific 1 kb regulatory element while Tcf7-expressing dendritic cells do not depend on this element for expression. The initiation of Tcf7 expression in T cells requires Notch binding sites while innate lymphoid cells do not need these sites.
TCF7 Expression Blocks Both Migration and Invasion Capabilities of Colorectal Cancer Cells
Colorectal cancer continues to show a poor prognosis because of its frequent metastasis. Research demonstrates that lncTCF7 functions as a key factor in human CRC development but its precise molecular operations in CRC have yet to be identified. Analysis of lncTCF7 reveals its impact on CRC cell migration and invasion together with its underlying molecular mechanisms. The expression levels of lncTCF7 were significantly higher in CRC cell lines than in normal colon epithelial cells. The suppression of lncTCF7 expression led to reduced migration and invasion capabilities in CRC cells. The TCF7 gene exhibited high expression levels in CRC cell lines relative to normal colon epithelial cells and experienced significant expression reduction following si-lncTCF7 transfection into CRC cells. Experiments using RNA immunoprecipitation, chromatin immunoprecipitation and luciferase reporter gene assays demonstrated how LncTCF7 recruited BAF170 to activate the TCF7 promoter which led to the regulation of TCF7 expression. TCF7 overexpression increased CRC cell migration and invasion in cells with si-lncTCF7 transfection which reversed lncTCF7 effects on cell movement and invasion.
TCF7 Participates in Important Physiological Activities
The identification of common regulatory elements that specifically control Tcf7 activation in T cells and ILCs further confirms the striking developmental and functional similarities between these two lineages. TCF7 plays a dual role in promoting the expression of genes characteristic of self-renewing CD34+ cells while repressing genes activated in the partially differentiated CD34− state. Thermogenic coactivator PRDM16 and histone demethylase LSD1 may be required for TCF7 activity. Many transcriptional similarities between T cells and ILCs include the control of Tcf7 by shared regulatory elements and further identify that lymphocytes and cDCs differ in the regulatory elements that control Tcf7 expression. TCF7 has important regulatory roles in cell biology and developmental biology, and its functions may be diverse in different physiological and pathological states.
References
- Wu, J., et al. Tcf7 is an important regulator of the switch of self-renewal and differentiation in a multipotential hematopoietic cell line. PLoS genetics. 2012, 8(3): e1002565.
- Harly, C., et al. A shared regulatory element controls the initiation of Tcf7 expression during early T cell and innate lymphoid cell developments. Frontiers in immunology. 2020, 11: 470.
- Wu, B., et al. Down-regulation of lncTCF7 inhibits cell migration and invasion in colorectal cancer via inhibiting TCF7 expression. Human Cell. 2019, 32: 31-40.
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