On the Self-Assembly of Brush Block Copolymers in Thin Films

We describe a simple route to fabricate two dimensionally well-ordered, periodic nanopatterns using the self-assembly of brush block copolymers (brush BCPs). Well-developed lamellar microdomains oriented perpendicular to the substrate are achieved, without modification of the underlying substrates, and structures with feature sizes greater than 200 nm are generated due to the reduced degree of chain entanglements of brush BCPs. A near-perfect linear scaling law was found for the period, L, as a function of backbone degree of polymerization (DP) for two series of brush BCPs. The exponent increases slightly from 0.99 to 1.03 as the side chain molecular weight increases from 2.4 to 4.5 kg/mol^(–1) and saturated with further increase in the side chain molecular weight due to the entropic penalty associated with the packing of the side chains. Porous templates and scaffolds from brush BCP thin films are also obtained by selective etching of one component

SUMO1 negatively regulates BRCA1-mediated transcription, via modulation of promoter occupancy

BRCA1, a tumor suppressor gene, is implicated in the repression and activation of transcription via interactions with a diverse range of proteins. The mechanisms regulating the action of BRCA1 are not fully understood. Here, we use the promoters of Gadd45α, p27KIP1 and p21WAF1/CIP1 to demonstrate that SUMO1 represses transactivation potential of BRCA1 by causing BRCA1 to be released from the promoters and augmenting histone deacetylation via recruitment of histone deacetylase (HDAC) activity. Consistently, silencing of SUMO1 led to recruitment of BRCA1 and release of HDAC1 at the BRCA1 target promoters, and subsequent transcriptional activation of the BRCA1 target genes. Furthermore, a sumoylation-incompetent mutant missing the sumoylation donor site suppressed BRCA1-induced activation of transcription, whereas E2 UBC9 or the dominant-negative mutant UBC9 had no effect, implying that repression of BRCA1-mediated activation of transcription by SUMO1 is independent of sumoylation. Repression of BRCA1-mediated activation of transcription by SUMO1 was reversed by DNA damage by inducing the release of SUMO1 from the Gadd45α promoter and the recruitment of BRCA1, along with increased histone acetylation, to enhance activation of transcription. Together, our data provide evidence that SUMO1 plays a role in the activation-repression switch of BRCA1-mediated transcription via modulation of promoter occupancy

Reducing the Size Sale of the Block Copolymer Microdomains and Morphology Study of Brush Block Copolymers Containing Homopolymer

Block copolymers (BCPs), due to their ability to self-assemble into periodic nanoscale morphologies, have been extensively studied over the past few decades. The thermodynamic parameters governing self-assembly of BCPs generally leads to periodic morphologies with characteristic length scales ranging from 10 to 100 nm. Several applications have been demonstrated utilizing BCPs as a template for the fabrication of nanostructured materials. Fabricating structures beyond the 10-100 nm range, remains a challenge and constitutes one of the goals of the proposed research. This dissertation is divided into two parts. The first focuses on the sub 10 nm length scale, when by chemically converting one of the blocks of the BCP, segmental interactions can be made extremely non-favorable, enabling smaller size scale structure to be achieved. The second is related to the study of brush block copolymers (BrBCPs) that can produce structured with characteristic length scales that can span from the sub-10 nm to 100s of nm. In first part, poly (styrene-b-solketal methacrylate) (PS-b-PSM) was investigated to generate the highly ordered microphase separated structures with deep sub 10 nm period. This novel BCP contains the solketal group which can be hydrolyzed readily into the glyceryl group in dry state under acidic conditions. The phase-mixed PS-b-PSM BCPs were forced into highly ordered lamellae microdomain of poly(styrene-b-glyceryl methacrylate) (PS-b-PGM) by substantial increase of Flory-Huggins segmental interaction parameter by the acid triggered hydrolysis reaction. The weakly segregated microdomains of the PS-b-PSM was successfully driven into the strongly segregated regime microdomains of the PS-b-PGM. Highly ordered lamellae microdomain of the PS-b-PGM with deep sub 10 nm domain size was achieved in thin film by conversion in dry state from the precursor PS-b-PSM thin films. The lamellae microdomain orientation was controlled into perpendicularly oriented to the substrate by novel design of conversion BCP thin film in a gradient manner. In second part, BrBCPs blends containing homopolymers in bulk and thin films were investigated. BrBCPs have been achieved great attention to achieve microphase separated structures with extremely large microdomain size over 100 nm readily compared to the conventional linear BCP. Its unusual rigid-like structure from the densely-grafted side chains to the backbone can prohibit it from the chain entanglement so as to provide the fast kinetics of the self-assembly. By adding homopolymers to the BrBCPs, the microdomain size was further increased. The morphologies and microdomain size of BrBCPs blends with homopolymers were studied using small angle x-ray scattering measurement. Perdeuterated homopolymers were used to detect the exact location and distribution of homopoymers in thin films by performing neutron reflectivity. It was evaluated of the distance and the interfacial width of microdomains of BrBCP blends by mixture of homopolymers as a function of the size and the amount of homopolymers

SUMO1 negatively regulates BRCA1-mediated

transcription, via modulation of promoter occupanc

The histone deacetylase inhibitor trichostatin A sensitizes estrogen receptor alpha-negative breast cancer cells to tamoxifen

Many cases of breast cancer show loss of estrogen receptor (ER) alpha expression, which leads to unresponsiveness to antihormonal treatment even though there is no loss of the structurally and biochemically similar ER beta. ER activity is positively and negatively regulated by transcriptional regulators such as histone deacetylase (HDAC), which is known to be a negative ER regulator. Here, we evaluated using ER beta as an alternative target for tamoxifen therapy by treating ER alpha-negative, beta-positive breast cancer cells with the HDAC inhibitor trichostatin A (TSA), and testing whether tamoxifen responsiveness increased following upregulation of ER beta. TSA enhanced the overall ER transcriptional activity in these cells, as visualized by estrogen response element-regulated reporter and the expression of progesterone receptor, a known ER target, without ER alpha restoration. Additionally, TSA induced the expression and nuclear translocation of ER beta but not alpha, suggesting that these actions leading to increase of ER transcriptional activity are mediated through ER beta rather than alpha. Furthermore, following treatment with TSA, the formerly unresponsive MDA-MB-231 and Hs578T breast cancer cells became responsive to tamoxifen. However, reduction of ER beta expression by short interfering RNA abrogated this TSA-induced sensitization effect in these cells. Together, these results show that the HDAC inhibitor TSA sensitized ER alpha-negative, antihormone-unresponsive breast cancer cells to tamoxifen treatment possibly by upregulating ER beta activity