The Role of Chromatin Density in Cell Population Heterogeneity during Stem Cell Differentiation

Abstract We incorporate three-dimensional (3D) conformation of chromosome (Hi-C) and single-cell RNA sequencing data together with discrete stochastic simulation, to explore the role of chromatin reorganization in determining gene expression heterogeneity during development. While previous research has emphasized the importance of chromatin architecture on activation and suppression of certain regulatory genes and gene networks, our study demonstrates how chromatin remodeling can dictate gene expression distribution by folding into distinct topological domains. We hypothesize that the local DNA density during differentiation accentuate transcriptional bursting due to the crowding effect of chromatin. This phenomenon yields a heterogeneous cell population, thereby increasing the potential of differentiation of the stem cells

Temporal evolution of human autoantibody response to cytoplasmic rods and rings structure during anti-HCV therapy with ribavirin and interferon-α

Autoantibodies to inosine monophosphate dehydrogenase-2 (IMPDH2), an enzyme involved in de novo biosynthesis of guanine nucleotides, are observed in a subset of hepatitis C virus (HCV) patients receiving interferon alpha (IFN-alpha) plus ribavirin. Anti-IMPDH2 antibodies display a peculiar cytoplasmic rod/ring (RR) pattern in IIF-HEp-2. We examined the dynamics of anti-RR autoimmune response with respect to immunoglobulin isotypes, titer, avidity, and protein targets in 80 sequential samples from 15 HCV patients (plus 12 randomly selected anti-RR-positive, totalizing 92 samples) collected over an 18-month period, including samples collected before, during, and after IFN-alpha + ribavirin treatment. Immunoprecipitation showed reactivity with the 55 kDa IMPDH2 protein in 12/15 patients (80 %) and 11/15 (73 %) reacted with IMPDH2 in a sandwich ELISA. During treatment, anti-IMPDH2 autoantibodies hit their highest levels after 6-12 months of treatment and decreased post-treatment, while anti-HCV antibodies levels were stable over time. Anti-IMPDH2 IgM levels increased up until the sixth month of treatment and remained stable thereafter, while IgG levels increased steadily up to the twelfth month. Both IgG and IgM decreased during the post-treatment period. IgG avidity increased steadily up to the twelfth month of treatment. in conclusion, this study showed that the temporal kinetics of IFN-alpha + ribavirin-induced humoral autoimmune response to IMPDH2 exhibited a considerably delayed pace of increase in antibody levels and avidity as well as in isotype class switch in comparison with a conventional humoral response to infectious agents. These unique findings uncover intriguing differences between the autoimmune response and the immune response to exogenous agents in humans.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo, Div Rheumatol, BR-04023062 São Paulo, BrazilUniv Florida, Dept Oral Biol, Gainesville, FL 32610 USAUniv Occupat & Environm Hlth, Sch Hlth Sci, Dept Clin Nursing, Yahata Nishi Ku, Kitakyushu, Fukuoka 8078555, JapanUniv Florida, Dept Med, Div Rheumatol & Clin Immunol, Gainesville, FL 32610 USAUniversidade Federal de São Paulo, Div Gastroenterol, BR-04023062 São Paulo, BrazilFleury Med & Hlth Labs, Div Immunol, BR-04102050 São Paulo, BrazilUniversidade Federal de São Paulo, Div Rheumatol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Div Gastroenterol, BR-04023062 São Paulo, BrazilFAPESP: 2010/50710-6FAPESP: 2011/12448-0CAPES: 9028-11-0CNPq: 305064/2011-8Web of Scienc