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1.
Front Cell Dev Biol ; 7: 141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396512

RESUMO

The dynamic architecture of chromatin, the macromolecular complex comprised primarily of DNA and histones, is vital for eukaryotic cell growth. Chemical and conformational changes to chromatin are important markers of functional and developmental processes in cells. However, chromatin architecture regulation has not yet been fully elucidated. Therefore, novel approaches to assessing chromatin changes at the single-cell level are required. Here we report the use of FTIR imaging and microfluidic cell-stretcher chips to assess changes to chromatin architecture and its effect on the mechanical properties of the nucleus in immune cells. FTIR imaging enables label-free chemical imaging with subcellular resolution. By optimizing the FTIR methodology and coupling it with cell segmentation analysis approach, we have identified key spectral changes corresponding to changes in DNA levels and chromatin conformation at the single cell level. By further manipulating live single cells using pressure-driven microfluidics, we found that chromatin decondensation - either during general transcriptional activation or during specific immune cell maturation - can ultimately lead to nuclear auxeticity which is a new biological phenomenon recently identified. Taken together our findings demonstrate the tight and, potentially bilateral, link between extra-cellular mechanotransduction and intra-cellular nuclear architecture.

2.
Front Immunol ; 9: 355, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29535729

RESUMO

Epigenetic modifications, such as histone modifications, DNA methylation status, and non-coding RNAs (ncRNA), all contribute to antibody maturation during somatic hypermutation (SHM) and class-switch recombination (CSR). Histone modifications alter the chromatin landscape and, together with DNA primary and tertiary structures, they help recruit Activation-Induced Cytidine Deaminase (AID) to the immunoglobulin (Ig) locus. AID is a potent DNA mutator, which catalyzes cytosine-to-uracil deamination on single-stranded DNA to create U:G mismatches. It has been shown that alternate chromatin modifications, in concert with ncRNAs and potentially DNA methylation, regulate AID recruitment and stabilize DNA repair factors. We, hereby, assess the combination of these distinct modifications and discuss how they contribute to initiating differential DNA repair pathways at the Ig locus, which ultimately leads to enhanced antibody-antigen binding affinity (SHM) or antibody isotype switching (CSR). We will also highlight how misregulation of epigenomic regulation during DNA repair can compromise antibody development and lead to a number of immunological syndromes and cancer.


Assuntos
Cromatina/metabolismo , Doenças do Sistema Imunitário/imunologia , Switching de Imunoglobulina , Neoplasias/imunologia , Hipermutação Somática de Imunoglobulina , Animais , Cromatina/genética , Citidina Desaminase/metabolismo , Reparo do DNA , Epigênese Genética , Histonas/metabolismo , Humanos , Doenças do Sistema Imunitário/genética , Imunidade Humoral , Neoplasias/genética , RNA não Traduzido/genética
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