A potential role for genome structure in the translation of mechanical force during immune cell development

Abstract

Immune cells react to a wide range of environments, both chemical and physical. While the former has been extensively studied, there is growing evidence that physical and in particular mechanical forces also affect immune cell behavior and development. In order to elicit a response that affects immune cell behavior or development, environmental signals must often reach the nucleus. Chemical and mechanical signals can initiate signal transduction pathways, but mechanical forces may also have a more direct route to the nucleus, altering nuclear shape via mechanotransduction. The three-dimensional organization of DNA allows for the possibility that altering nuclear shape directly remodels chromatin, redistributing critical regulatory elements and proteins, and resulting in wide-scale gene expression changes. As such, integrating mechanotransduction and genome architecture into the immunology toolkit will improve our understanding of immune development and disease.

Keywords: Hi-C; chromatin; genome biology; immune; mechanosensory; mechanotransduction; nuclear lamin; nucleoskeleton; nucleus; tensegrity.

Figure 1.

Tensegrity architecture coordinates responses to mechanical signals. Cell surface receptors are mechanically linked to the nucleus via the cytoskeleton and LINC complex. These inter-connected skeletons can transduce mechanical signals, including fluid shear stress to rapidly remodel the cyto- and nucleo-skeletons.

Figure 2.

Immune cells are exposed to a variety of mechanical environments. (A) During development in the bone marrow, Haematopoietic stem cells (HSCs) divide symmetrically (i) in the soft marrow, but divide asymmetrically upon reaching the stiff matrix (ii); one daughter cell maintains stemness, while the other begins differentiation. The differentiating cell migrates into the blood vessel by squeezing through the endothelial cell layer, which deforms the nucleus (iii). The cell is then subject to fluid shear stress in the blood stream (iv). This step is particularly important for the development of megakaryocytes into platelets. (B) During inflammation, the matured immune cell must then extravasate to enter the infected tissue. To migrate through the endothelial cell layer, the cell first makes contact with the endothelial cells (rolling adhesion, (i)), then becomes more strongly adherent (firm adhesion, (ii)), and finally undergoes diapedesis (iii). After successful migration, the cell may be exposed to a range of tissue microenvironments (iv,v). Finally, the cell may return to the blood stream (C), again deforming the nucleus to migrate through the endothelial cell layer, and once again becoming exposed to fluid shear stress.

Figure 3.

Chromatin architecture may translate mechanical forces to gene expression changes. Changes in nuclear shape may affect nuclear activity in several ways. The most simple model (A) shows repositioning of DNA relative to a transcription factory; the purple and green chromosomal regions alternate activity based on the proximity of the transcription factory. Due to the constant binding and unbinding of proteins to DNA, these changes are rapidly reversible and may not be maintained in the absence of the force in either the structure or the function of the nucleus. (B) Some chromatin remodelling proteins are known to ‘slide’ along DNA. Therefore, pulling on chromatin loops brings 2 or more proteins into close proximity, forming the complexes necessary to initiate transcription. This may result in a stable change to both genome organization and function. (C) Changes in nuclear shape may bring a modifier and its target into contact, allowing a transient change to chromatin architecture to result in a stable change to nuclear function. For simplicity, SUMOylation has been illustrated as the post-translational modification (PTM) of the transcription factor, shown here tethered to the nuclear lamina. Transcription factors and other accessory proteins have SUMO (Small Ubiquitin-like Modifier), ubiquitin, or other PTMs delivered by modifiers which are often tethered to chromatin or nucleoskeleton components. These modifications may activate or repress transcriptional activity, or target the protein for degradation..