Transcriptional activation of genes within the nucleus of eukaryotic cells occurs by a variety of mechanisms. Typically, these mechanisms rely on the interaction of regulatory proteins (transcriptional activators or repressors) with specific DNA sequences that control gene expression. Upon DNA binding, regulatory proteins also interact with other proteins that are part of the RNA polymerase II transcriptional complex.
One type of transcriptional activation relies on inducing a conformational change in chromatin, the DNA-protein complex that makes up each chromosome within a cell. In a broad sense, “extended” or loosely wound chromatin is more accessible to transcription factors and can signify an actively transcribed gene. In contrast, “condensed” chromatin hinders access to transcription factors and is characteristic of a transcriptionally inactive state. Acetylation of lysine residues in histones—the primary constituents of the chromatin backbone—results in opening up the chromatin and consequent gene activation. Disruption of histone acetylation pathways is implicated in many types of cancer (1).
DNA is organized by protein:DNA complexes called nucleosomes in eukaryotes. Nucleosomes are composed of 147 base pairs of DNA wrapped around a histone octamer containing two copies of each core histone protein. Histone proteins play significant roles in many nuclear processes including transcription, DNA damage repair and heterochromatin formation. Histone proteins are extensively and dynamically post-translationally modified, and these post-translational modifications (PTMs) are thought to comprise a specific combinatorial PTM profile of a histone that dictates its specific function. Abnormal regulations of PTM may lead to developmental disorders and disease development such as cancer.
The ability to isolate and assay circulating cell-free DNA from plasma holds promise for improved diagnostics and treatment in the clinic. The use of blood-based non-invasive prenatal testing (NIPT) has been well described. Such testing is based on circulating cell-free fetal DNA in blood of a pregnant woman for diagnosis and screening of chromosomal anueploidy (e.g. Trisomy 21, Down Syndrome), sex-linked diseases, and genetic diseases that are known to result from a specific mutation in a single gene (1). Additionally, most cancers carry somatic mutations that are unique to the tumors, and dying tumor cells release small pieces of their DNA into the blood stream (2). This circulating cell-free tumor DNA can be used as a biomarker to “follow” cancer progression or regression during treatment, and diagnostic methods also are being developed to detect even early stage cancers from circulating tumor DNA (3). Further, increases in circulating cell-free DNA have been well documented after intense exercise, trauma, sepsis and even associated with autoimmune diseases such as system lupus erythematosus (SLE; 1,4). In these latter examples increases in extracellular DNA are associated with evolutionarily conserved innate immune responses involving the production of neutrophil extracellular traps (NETs). Monitoring the circulating cell-free DNA of NETs has implications for treatment and diagnosis of autoimmune diseases, cardiovascular events and traumatic injuries (4–7).
How Neutrophils Weave a Defensive Web
Neutrophils are the most abundant type of white blood cell and are part of the innate immune response, participating in non-specific immune responses to injury or pathogens. They are one of three types of granuolcytes, and can be recognized by their multi-lobed nucleus and the prominent granules that fill their cytoplasm. Generally they are first to the scene of injury or infection. Early in my scientific career, I was taught that neutrophils fought disease via phagocytosis and occasionally by firing a barrage of toxic enzymes and molecules at invaders. Mostly though they released cytokines that recruited the “important” cells of the specific immune system to the area.
For these reasons, I never really thought much about neutrophils. That is until recently, when I learned about Neutrophil Extracellular Traps (NETs). It turns out that neutrophils are pretty awesome, sacrificing themselves in a cloud-like explosion of DNA, chromatin, and granule proteins
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