The successful integration of nanoparticles into biomedical applications requires modulation of their surface properties so that the interaction with biological systems is regulated to minimize toxicity for biological function. In the present work, we have engineered bioactive surfaces on gold (Au) and silver (Ag) nanoparticles and subsequently evaluated their interaction with mouse skin fibroblasts and macrophages. The Au and Ag nanoparticles were synthesized using tyrosine, tryptophan, isonicotinylhydrazide, epigallocatechin gallate, and curcumin as reducing and stabilizing agents. The nanoparticles thus prepared showed surface corona and exhibited free radical scavenging and enzyme activities with limited cytotoxicity and genotoxicity. We have thus developed avenues for engineering the surface of nanoparticles for biological applications.

MicroRNAs (miRNAs) may modulate more than 60% of human coding genes and act as negative regulators, while long non-coding RNAs (lncRNAs) regulate gene expression on multiple levels by interacting with chromatin, functional proteins, and RNAs such as mRNAs and microRNAs. However, the crosstalk between HOTTIP lncRNA and miRNAs in leukemogenesis remains elusive. Using combined integrated analyses of global miRNA expression profiling and state-of-the-art genomic analyses of chromatin such as ChIRP-seq ( HOTTIP binding in genome-wide), ChIP-seq, and ATAC-seq, we found that some miRNA genes are directly controlled by HOTTIP. Specifically, the HOX cluster miRNAs (miR-196a, miR-196b, miR-10a and miR-10b), located cis & trans , were most dramatically regulated and significantly decreased in HOTTIP −/− AML cells. HOTTIP bound to the miR-196b promoter, and HOTTIP deletion reduced chromatin accessibility and enrichment of active histone modifications at HOX cluster associated miRNAs in AML cells, while reactivation of HOTTIP restored miR gene expression and chromatin accessibility in the CTCF-boundary-attenuated AML cells. Inactivation of HOTTIP or miR-196b promotes apoptosis by altering the chromatin signature at the FAS promoter and increasing FAS expression. Transplantation of miR-196b knockdown MOLM13 cells in NSG mice increased overall survival of mice compared to wild-type cells transplanted into mice. Thus, HOTTIP remodels the chromatin architecture around miRNAs to promote their transcription, and consequently represses tumor suppressors and promotes leukemogenesis.

MicroRNAs (miRNAs) may modulate more than 60% of human coding genes and act as negative regulators, while long non-coding RNAs (lncRNAs) regulate gene expression on multiple levels by interacting with chromatin, functional proteins, and RNAs such as mRNAs and microRNAs. However, the crosstalk between lncRNA HOTTIP and miRNAs in leukemogenesis remains elusive. Using combined integrated analyses of global miRNA expression profiling and state-of-the-art genomic analyses of chromatin such as ChIRPseq., (genome wide HOTTIP binding analysis), ChIP-seq., and ATACseq., we found that miRNA genes are directly controlled by HOTTIP. Specifically, the HOX cluster miRNAs (miR-196a, miR-196b, miR-10a and miR-10b), located cis & trans, were most dramatically regulated and significantly decreased in HOTTIP knockout (KO) AML cells. HOTTIP bound to the miR-196b promoter, and HOTTIP deletion reduced chromatin accessibility and enrichment of active histone modifications at HOX cluster associated miRNAs in AML cells, while reactivation of HOTTIP restored miR gene expression and chromatin accessibility in the CTCF-boundary-attenuated AML cells. Inactivation of HOTTIP or miR-196b promotes apoptosis by altering the chromatin signature at the FAS promoter and increasing FAS expression. Transplantation of miR-196b knockdown MOLM13 cells in NSG mice increased overall survival compared to wild-type cells. Thus, HOTTIP remodels the chromatin architecture around miRNAs to promote their transcription, consequently repressing tumor suppressors and promoting leukemogenesis.