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SRX2499499: GSM2461023: RNASeq_DP_ctrl_2; Mus musculus; RNA-Seq
1 ILLUMINA (Illumina HiSeq 3000) run: 19.7M spots, 987.2M bases, 282.3Mb downloads

Submitted by: NCBI (GEO)
Study: Integrative analysis of 3D nucleome and chromatin accessibility reveals a chromatin barrier established for T-lineage commitment during early T cell development [Dnase-Seq, HiC-Seq, Mnase-Seq, RNA-Seq]
show Abstracthide Abstract
Hematopoiesis consists of step-wise commitment of multiple distinct intermediate differentiation stages before mature blood cells are generated. Although extensive studies have been performed on regulatory pathways in mature blood cells, few have examined chromatin reorganization underlying the changes in transcription programs from early progenitors of hematopoiesis to mature immune cells. In particular, what roles chromatin organization plays in the cell fate commitment during the differentiation of early hematopoietic progenitor cells to committed T cells remains unclear. Here, we carried out an integrative analysis of 3D nucleome, chromatin accessibility and gene expression from hematopoietic stem cells (HSC) to CD4/CD8 double positive (DP) T cells. Analysis of these data sets revealed extensive reorganization of A/B compartments, topologically associating domains (TADs), and chromatin accessibility at transcriptional regulatory regions during the development process. Remarkably, all three levels of chromatin organization display a monotonic pattern of change. While gradual and progressive changes in chromatin reorganization was observed at most development stages, an abrupt genome-wide change in A/B compartment structure, TAD domain scores and chromatin accessibility occurred during the transition from double negative stage 2 (DN2) to DN3, which was accompanied with the loss of cell fate plasticity of DN3 to differentiate to alternative lineages, suggesting that a chromatin barrier is established at the DN3 stage to lock the cells in the T cell fate. This chromatin barrier may be reinforced by another genome-wide reorganization of chromatin at the DN4-to-DP transition. The binding of PU.1, a key factor for the fate choice of early progenitor cells, and BCL11B, critically required for T cell commitment at later stages, was associated with increased long-distance interaction and chromatin accessibility. Deletion of Bcl11b led to decreased chromatin interaction for BCL11B target genes, suggesting that it may contribute to the establishment of the 3D nucleome structure required for the lineage differentiation and commitment. Overall design: To understand the contribution of chromatin interaction landscape to early development stages of hematopoesis, we generated genome-wide profiles of chromatin interaction (with an improved HiC protocal), chromatin accessibility (with scDNase-Seq) and gene expression (with RNA-Seq) from hematopoietic stem cells (HSC) and its immediate progeny (MPP) to common lymphocyte progenitor cells (CLP), early T progenitor cells (ETP or DN1), double negative stage 2 (DN2), DN3, DN4 and double positive (DP) cells. To examine the impact of BCL11B on gene expression, we conditionally knocked out Bcl11b in DP cells and mearured the expression change by RNA-Seq. To examine the effect of BCL11B on chromatin interaction and accessibility, we conditional knocked out Bcl11b in Naive CD4+ T cells and measured change in chromatin interaction by Hi-C, chromatin accessibility by scDNase-Seq, and expression by RNA-Seq.
Sample: RNASeq_DP_ctrl_2
SAMN06237484 • SRS1926229 • All experiments • All runs
Organism: Mus musculus
Library:
Instrument: Illumina HiSeq 3000
Strategy: RNA-Seq
Source: TRANSCRIPTOMIC
Selection: cDNA
Layout: SINGLE
Construction protocol: For Hi-C, five thousands to millions cells were stained with Biotin anti-CD45.2 antibody. Cells were bound to biotin binder (Dynabeads Biotin Binder, Cat#11047, Invitrogen) and cross-link with 1% formaldehyde. Biotin binders were blocked by 0.5mM biotin solution. Cells were lysed and digested with CviQ I + CviA II + Bfa I for 20min. For DNase-Seq, 1000 purified cells were lysed in 32ul of lysis buffer (10mM Tris-Cl, pH7.5, 10mM NaCl, 3mM MgCl2) and digested with 8ul of DNase I for 5 min at 37°C. The reaction was stopped by adding 40ul of stop buffer containing 10mM Tris-Cl, pH7.5, 10mM NaCl, 10mM EDTA, 2% SDS, 0.5mg/ml Proteinase K, and 1ng/ul of circular carrier DNA), followed by incubation at 65°C for 1 hour. For MNase-Seq, 100 purified cells were lysed in 32ul of lysis buffer (10mM Tris-Cl, pH7.5, 10mM NaCl, 2mM CaCl2) and digested with 8ul of MNase I for 5 min at 37°C. The reaction was stopped by adding 40ul of stop buffer containing 10mM Tris-Cl, pH7.5, 10mM NaCl, 10mM EGTA, 2% SDS, 0.5mg/ml Proteinase K, and 1ng/ul of circular carrier DNA), followed by incubation at 65°C for 1 hour. For RNA-Seq, 2ng of total RNA were extracted miRNeasy Micro Kit (50) from Qiagen (Cat # 217084). The Hi-C samples were processed following the Hi-C protocol (PMID 19815776) with modifications briefly described as follows: DNA end were marked by biotin-14-dATP with Klenow(larg) for 1hrs at 37°C. Blunt-end DNA were ligated with T4 DNA Ligase for overnight at 16°C. DNA were reverse cross-linked and purified by phenol/chloroform extraction. Biotin were removed from unligated DNA-ends by T4 DNA polymerase for 2hrs at 12°C. DNA were purified by phenol/chloroform. DNA were sheared to 300-500bps by sonication and flowed by DNA-end repair and add”A”34. Biotin labeled DNA were pull-downed by streptavidin beads and then flowed by illumine adapter ligation and PCR amplification. Library construction protocals for DNase-Seq, MNase-Seq and RNA-Seq follow that described in (PMID 26605532), (PMID 18329373) and (PMID 24056875), respectively.
Experiment attributes:
GEO Accession: GSM2461023
Links:
Runs: 1 run, 19.7M spots, 987.2M bases, 282.3Mb
Run# of Spots# of BasesSizePublished
SRR518344319,743,051987.2M282.3Mb2018-02-20

ID:
3623025

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