Hematopoietic stem cells (HSCs) exhibit functional alterations, such as reduced regenerative capacity and myeloid-biased differentiation, with age. The HSC niche, which is essential for the maintenance of HSCs, also undergoes marked changes with aging. However, it has been technically challenging to directly evaluate the contribution of niche aging to age-associated HSC alterations without niche-damaging myeloablation in HSC transplantation assays. We herein transplanted an excess of aged HSCs into young mice without preconditioning. Although aged HSCs successfully engrafted in the intact young bone marrow niche, they poorly regenerated downstream progenitors and exhibited persistent myeloid-biased differentiation, resulting in no significant functional rejuvenation. Transcriptome and methylome analyses revealed that the young niche largely restored the transcriptional profile of aged HSCs, but not their DNA methylation profiles. Therefore, the restoration of the young niche is insufficient for rejuvenating HSC functions, highlighting a key role for age-associated cell-intrinsic defects in HSC aging.

TET2 functions as a resistance factor against DNA methylation acquisition during Epstein-Barr virus infection

• The entire landscape of AR-V7 target regions/genes in CRPC cells was investigated. • We identified 78 AR-V7 target genes, targeted specifically by AR-V7 e.g. SLC3A2, or commonly by AR and AR-V7 e.g. NUP210. • SLC3A2 and NUP210 were markedly upregulated in clinical CRPC tissues, leading to increased proliferation in CRPC.

The far-upstream element-binding protein-interacting repressor (FIR) is a c-myc transcriptional suppressor. FIR is alternatively spliced to lack the transcriptional repression domain within exon 2 (FIRΔexon2) in colorectal cancers. FIR and FIRΔexon2 form homo- or heterodimers that complex with SAP155. SAP155, a subunit of the essential splicing factor 3b subcomplex in the spliceosome, is required for proper P27Kip1 pre-mRNA splicing, and P27Kip1 arrests cells at G1. In contrast, FIR was co-immunoprecipitated with Ku86 and DNA-PKcs. siRNA against Ku86/Ku70 decreased FIR and P27Kip1 expression, whereas siRNA against FIR decreased Ku86/XRCC5 and P27Kip1 expression. Thus the mechanical interaction of FIR/FIRΔexon2/SAP155 bridges c-myc and P27Kip1 expression, potentially integrates cell-cycle progression and c-myc transcription in cell.

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Sohei Kobayashi1, Tyuji Hoshino2, Takaki Hiwasa3, Mamoru Satoh4, Bahityar Rahmutulla1, 5, Sachio Tsuchida4, Yuji Komukai2, Tomoaki Tanaka1, Hisahiro Matsubara6, Hideaki Shimada7, Fumio Nomura4, Kazuyuki Matsushita1, 8 1Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba City, Chiba 260-8670, Japan 2Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan 3Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan 4Divisions of Clinical Mass Spectrometry and Clinical Genetics, Chiba University Hospital, Chiba 260-8670, Japan 5Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba City, Chiba 260-8670, Japan 6Department of Academic Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan 7Department of Gastroenterological Surgery, Toho University Omori Medical Center, Tokyo 143-8541, Japan 8Department of Laboratory Medicine & Division of Clinical Genetics and Proteomics Chiba University Hospital, Chiba 260-8670, Japan Correspondence to: Kazuyuki Matsushita, email: kmatsu@faculty.chiba-u.jp Keywords: auto-antibodies, cancer biomarker, colorectal cancer, far-upstream element-binding protein-interacting repressor (FIR) = poly(U)-binding-splicing factor (PUF60) Received: June 29, 2016 Accepted: October 12, 2016 Published: October 15, 2016 ABSTRACT Anti-PUF60, poly(U)-binding-splicing factor, autoantibodies are reported to be detected in the sera of dermatomyositis and Sjogren’s syndrome that occasionally associated with malignancies. PUF60 is identical with far-upstream element-binding protein-interacting repressor (FIR) that is a transcriptional repressor of c-myc gene. In colorectal cancers, a splicing variant of FIR that lacks exon2 (FIRΔexon2) is overexpressed as a dominant negative form of FIR. In this study, to reveal the presence and the significance of anti-FIRs (FIR/FIRΔexon2) antibodies in cancers were explored in the sera of colorectal and other cancer patients. Anti-FIRs antibodies were surely detected in the preoperative sera of 28 colorectal cancer patients (32.2% of positive rates), and the detection rate was significantly higher than that in healthy control sera (Mann–Whitney U test, p < 0.01). The level of anti-FIRs antibodies significantly decreased after the operation (p < 0.01). Anti-FIRs antibodies were detected in the sera of early-stage and/or recurrent colon cancer patients in which anti-p53 antibodies, CEA, and CA19-9 were not detected as well as in the sera of other cancer patients. Furthermore, the area under the curve of receiver operating characteristic for anti-FIRs antibodies was significantly larger (0.85) than that for anti-p53 antibodies or CA19-9. In conclusions, the combination of anti-FIRs antibodies with other clinically available tumor markers further improved the specificity and accuracy of cancer diagnosis.