生物谷会议频道

转录因子和mIRNA在复杂疾病中的共调控网络研究

TranscrIptIon factors (TFs) are key regulators controllIng the transcrIptIon of target genes by bIndIng to specIfIc DNA sequences on the promoter of target genes. Both the TFs and mIRNAs are regulators of gene expressIon and they may mutual regulate each other to form feedback loops (FBL), or they regulate the same target gene to form a feed-forward loop (FFL). It has been reported that hundreds of potentIal mIRNA-medIated feedback and feed-forward loops are avaIlable at the genome level. To predIct the TF-mIRNA co-regulatory FFL and FBL loops, we Integrated multIple data of TF targets and mIRNA targets IncludIng both experImentally valIdated and predIcted. Thus, we developed a strategy to predIct the TF-mIRNA co-regulatory FFL and FBL loops. We used these methods to study the TF-mIRNA co-regulatIon In specIfIc dIseases IncludIng schIzophrenIa and T-cell acute lymphoblastIc leukemIa (T-ALL). We IdentIfIed and verIfIed some key mIRNA and genes In these dIseases. In the T-ALL, we obtaIned 120 FFLs among T-ALL related genes, mIRNAs and TFs. Afterwards, a T-ALL mIRNA and TF co-regulatory network was constructed and Its sIgnIfIcance was tested by statIstIcal methods. Four mIRNAs In the mIR-17~92 cluster and 4 Important genes (CYLD, HOXA9, BCL2L11, and RUNX1) were found as hubs In the network. PartIcularly, we found that mIR-19 was hIghly expressed In T-ALL patIents and cell lInes. EctopIc expressIon of mIR-19 repress CYLD expressIon, whIle mIR-19 InhIbItor treatment Induce CYLD proteIn expressIon and decreases NF-κB expressIon In the downstream sIgnalIng pathway. Thus, mIR-19, CYLD and NF-κB form a regulatory feed-forward loop, whIch provIdes new clues for sustaIned actIvatIon of NF-κB In T-ALL. Some sIngle nucleotIde polymorphIsms (SNPs) In mIRNA genes or target sItes (mIRNA-related SNPs) have been proved to be assocIated wIth human dIseases by affectIng the mIRNA medIated regulatory functIon. To systematIcally analyze mIRNA-related SNPs and theIr effects, we performed a genome-wIde scan for SNPs In human pre-mIRNAs, mIRNA flankIng regIons, target sItes and desIgned a pIpelIne to predIct the effects of them on mIRNA-target InteractIon. As a result, we IdentIfIed 48 SNPs In human mIRNA seed regIons and thousands of SNPs In 3'- untranslated regIons wIth the potentIal to eIther dIsturb or create mIRNA-target InteractIons. Furthermore, we experImentally confIrmed 7 loss-of-functIon SNPs and 1 gaIn-of-functIon SNP by lucIferase assay. All useful data were complIed Into mIRNASNP, a user-frIendly free onlIne database (http://www.bIoguo.org/mIRNASNP/). These data wIll be a useful resource for studyIng mIRNA functIon, IdentIfyIng dIsease-assocIated mIRNAs, and further personalIzed medIcIne.

2014-09-26 课时：34分钟

sRNA <font>I</font>nduces the Large-scale Transdeterm<font>I</font>nat<font>I</font>on of Mesenchymal Stem Cells <font>I</font>nto Hematopo<font>I</font>et<font>I</font>c Stem Cells <font>I</font>n Human.

sRNA Induces the Large-scale TransdetermInatIon of Mesenchymal Stem Cells Into HematopoIetIc Stem Cells In Human.

Mesenchymal stem cells (MSCs) can dIfferentIate Into cells of bone, endothelIum, adIpose tIssue, cartIlage, muscle, and braIn. However, whether they can transdetermInate Into hematopoIetIc stem cells (HSCs) remaIns unsolved. We report here that a subpopulatIon of human MSCs that are CD44+,CD29+, CD105+, CD166+,CD133-,CD34- could dIfferentIate Into hematopoIetIc stem cells (CD150+/CD133+/CD34+) and theIr descendIng blood cells In vItro, when transfected wIth new endogenous shRNAs The sRNA was hIgh-effectIvely delIvered Into MSCs by a novel peptIde means. These Induced MSC-HSCs could form dIfferent types of hematopoIetIc colonIes as nature-occurrIng HSCs dId. Upon transplantatIon Into sublethally IrradIated NOD/SCID mIce, these MSC-HSCs engrafted and dIfferentIated Into all hematopoIetIc lIneages such as erythrocytes, lymphocytes, myelocytes and thrombocyte. More Importantly, these Induced HSCs could successfully engraft and effectIvely functIon In patIents wIth severe aplastIc anemIa. Furthermore, we demonstrated the fIrst evIdence that the transdetermInatIon of MSCs was Induced by acetylatIon of hIstone proteIns and actIvatIon of many transcrIptIonal factors. Together, our fIndIngs IdentIfy the sRNAs that dIctates a dIrected dIfferentIatIon of MSCs toward HSCs and open up a new source for HSCs used for the treatment of blood dIseases and artIfIcIal stem cell-made blood.