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Investigation of the Transcriptional Role of a RUNX1 Intronic Silencer by CRISPR/Cas9 Ribonucleoprotein in Acute Myeloid Leukemia Cells
Published on: September 1, 2019
RUNX3 negatively regulates CD36 expression in myeloid cell lines
Amaya Puig-Kröger1, Angeles Domínguez-Soto, Laura Martínez-Muñoz
1Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas (CSIC), Ramiro de Maeztu 9, Madrid 28040, Spain.
Insights
RUNX3 transcription factor negatively regulates CD36 expression in myeloid cells. This regulation impacts dendritic cell maturation and immune responses, potentially preventing autoimmunity.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- CD36 is a scavenger receptor involved in lipoprotein binding, fatty acid uptake, and apoptotic cell recognition by mononuclear phagocytes.
- CD36 plays a role in preventing autoimmunity by impairing dendritic cell (DC) maturation and acts as a coreceptor for TLR2/6 in sensing microbial diacylglycerides.
- RUNX3 transcription factor is crucial for DC reprogramming and its deficiency leads to accelerated DC maturation.
Purpose of the Study:
- To investigate the regulatory relationship between RUNX3 transcription factor and CD36 expression in myeloid cells.
- To elucidate the molecular mechanisms by which RUNX3 influences CD36 gene regulation.
- To understand the implications of RUNX3-mediated CD36 down-regulation on immune cell function and autoimmune responses.
Main Methods:
- In vitro assays to assess RUNX3 binding to the CD36 gene regulatory region.
- In vivo studies to confirm RUNX3 occupancy of the CD36 gene locus.
- Overexpression of RUNX3 in myeloid cells to evaluate its effect on CD36 expression levels.
Main Results:
- RUNX3 transcription factor negatively regulates CD36 expression during myeloid cell differentiation and activation.
- RUNX3 directly impairs the proximal regulatory region of the CD36 gene by recognizing specific binding elements.
- RUNX3 occupies the CD36 gene regulatory region in vivo, and its overexpression significantly reduces CD36 expression.
Conclusions:
- RUNX3 acts as a negative regulator of CD36 expression in myeloid cells.
- RUNX3-mediated down-regulation of CD36 may impair the recognition of pathogens and apoptotic cells by mature DCs.
- This regulatory mechanism suggests a role for RUNX3 in mitigating autoimmune responses by modulating DC function.
Abstract:
CD36 is a member of the scavenger receptor type B family implicated in the binding of lipoproteins, phosphatidylserine, thrombospondin-1, and the uptake of long-chain fatty acids. On mononuclear phagocytes, recognition of apoptotic cells by CD36 contributes to peripheral tolerance and prevention of autoimmunity by impairing dendritic cell (DC) maturation. Besides, CD36 acts as a coreceptor with TLR2/6 for sensing microbial diacylglycerides, and its deficiency leads to increased susceptibility to Staphylococcus aureus infections. The RUNX3 transcription factor participates in reprogramming DC transcription after pathogen recognition, and its defective expression leads to abnormally accelerated DC maturation. We present evidence that CD36 expression is negatively regulated by the RUNX3 transcription factor during myeloid cell differentiation and activation. In molecular terms, RUNX3 impairs the activity of the proximal regulatory region of the CD36 gene in myeloid cells through in vitro recognition of two functional RUNX-binding elements. Moreover, RUNX3 occupies the CD36 gene proximal regulatory region in vivo, and its overexpression in myeloid cells results in drastically diminished CD36 expression. The down-regulation of CD36 expression by RUNX3 implies that this transcription factor could impair harmful autoimmune responses by contributing to the loss of pathogen- and apoptotic cell-recognition capabilities by mature DCs.
