CoREST has a conserved role in facilitating SPR-5/LSD1 maternal reprogramming of histone methylation

Maternal reprogramming of histone methylation is critical for reestablishing totipotency in the zygote, but how histone modifying enzymes are regulated during maternal reprogramming is not well characterized. To address this gap, we asked whether maternal reprogramming by the H3K4me1/2 demethylase SPR-5/LSD1/KDM1A, is regulated by the co-repressor protein, SPR-1/CoREST in C. elegans and mice. In C. elegans, SPR-5 functions as part of a reprogramming switch together with the H3K9 methyltransferase MET-2. By examining germline development, fertility and gene expression in double mutants between spr-1 and met-2, we find that spr-1 mutants are partially compromised for spr-5; met-2 reprogramming. In mice, we generated a separation of function Lsd1 M448V point mutation that compromises CoREST binding, but only slightly affects LSD1 demethylase activity. When maternal LSD1 in the oocyte is derived exclusively from this allele, the progeny phenocopy the increased perinatal lethality that we previously observed when LSD1 was reduced maternally. Together, these data are consistent with CoREST having a conserved function in facilitating maternal LSD1 epigenetic reprogramming.

Targeting the Aryl Hydrocarbon Receptor Signaling Pathway in Breast Cancer Development

Activation of the aryl hydrocarbon receptor (AhR) through environmental exposure to known human carcinogens including dioxins can lead to the promotion of breast cancer. While the repressor protein of the AhR (AhRR) blocks the canonical AhR pathway, the function of AhRR in the development of breast cancer is not well-known. In the current study we examined the impact of suppressing AhR activity using its dedicated repressor protein AhRR. AhRR is a putative tumor suppressor and is silenced in several cancer types, including breast, where its loss correlates with shorter patient survival. Using the AhRR transgenic mouse, we demonstrate that AhRR overexpression opposes AhR-driven and inflammation-induced growth of mammary tumors in two different murine models of breast cancer. These include a syngeneic model using E0771 mammary tumor cells as well as the Polyoma Middle T antigen (PyMT) transgenic model. Further AhRR overexpression or knockout of AhR in human breast cancer cells enhanced apoptosis induced by chemotherapeutics and inhibited the growth of mouse mammary tumor cells. This study provides the first in vivo evidence that AhRR suppresses mammary tumor development and suggests that strategies which lead to its functional restoration and expression may have therapeutic benefit.

Transcription Repressor Protein ZBTB25 Associates with HDAC1-Sin3a Complex in Mycobacterium tuberculosis-Infected Macrophages, and Its Inhibition Clears Pathogen by Autophagy

Following infection with M. tuberculosis , levels of HDAC1 go up in macrophages, and it is recruited to the promoter of IL-12B where it hypoacetylates histone H3, leading to the downregulation of the gene. Here, we show that host transcriptional repressor protein ZBTB25 and transcriptional corepressor Sin3a associate with HDAC1 in the silencing complex.

miRNA-mediated alteration of sulfatase modifying factor 1 expression using self-assembled branched DNA nanostructures

Reduced expression of SUMF1 was evidenced in MCF-7 cells transfected with antimiR-bDNA. Expression of miRNA-106 and 148 have positive correlation with the expression of SUMF1. miRNA-106 and 148 blocks the repressor protein controls SUMF-1 expression.

“Multiplex” rheostat positions cluster around allosterically critical regions of the lactose repressor protein

Amino acid variation at “rheostat” positions provides opportunity to modulate various aspects of protein function – such as binding affinity or allosteric coupling – across a wide range. Previously a subclass of “multiplex” rheostat positions was identified at which substitutions simultaneously modulated more than one functional parameter. Using the Miller laboratory’s dataset of ∼4000 variants of lactose repressor protein (LacI), we compared the structural properties of multiplex rheostat positions with (i) “single” rheostat positions that modulate only one functional parameter, (ii) “toggle” positions that follow textbook substitution rules, and (iii) “neutral” positions that tolerate any substitution without changing function. The combined rheostat classes comprised >40% of LacI positions, more than either toggle or neutral positions. Single rheostat positions were broadly distributed over the structure. Multiplex rheostat positions structurally overlapped with positions involved in allosteric regulation. When their phenotypic outcomes were interpreted within a thermodynamic framework, functional changes at multiplex positions were uncorrelated. This suggests that substitutions lead to complex changes in the underlying molecular biophysics. Bivariable and multivariable analyses of evolutionary signals within multiple sequence alignments could not differentiate single and multiplex rheostat positions. Phylogenetic analyses – such as ConSurf – could distinguish rheostats from toggle and neutral positions. Multivariable analyses could also identify a subset of neutral positions with high probability. Taken together, these results suggest that detailed understanding of the underlying molecular biophysics, likely including protein dynamics, will be required to discriminate single and multiplex rheostat positions from each other and to predict substitution outcomes at these sites.

The Role of Divalent Transition Metal Ions in the Binding of Fur Dimer to DNA: Binding of Mn2+ and Co2+ to EC Fur dimer-DNA Complex

Ferric uptake regulation protein is a repressor protein which binds an AT rich region of DNA (the iron box). Fur binds as a dimer in a helix turn helix mode and it is activated by iron(II) and other divalent transition metal ions at elevated concentrations in a process to regulate the ion uptake. Each transition metal ion induces certain conformational changes to aid the Fur binding, both the N-terminal and C-terminal domains take part in binding to DNA in addition to His 88 and His 86 residues. The process is discussed in view of experimental reports. Fe(II), Mn(II) and Co(II) activate Fur to bind DNA experimentally but Zinc plays a structural role and does not activate Fur to bind DNA.

The Role of Divalent Transition Metal Ions in the Binding of Fur Dimer to DNA: Binding of Mn2+ and Co2+ to EC Fur dimer-DNA Complex

Ferric uptake regulation protein is a repressor protein which binds an AT rich region of DNA (the iron box). Fur binds as a dimer in a helix turn helix mode and it is activated by iron(II) and other transition metal ions at elevated concentrations. Each transition metal ion induces certain conformational changes to aid the Fur binding, both the N-terminal and C-terminal domains take part in binding to DNA in addition to His 88 and His 86. The process is discussed in view of experimental reports. Fe(II), Mn(II) and Co(II) activate Fur to bind DNA but Zinc plays a structural role and does not activate Fur to bind DNA.

The Role of Divalent Transition Metal Ions in the Binding of Fur Dimer to DNA: Binding of Mn2+ and Co2+ to EC Fur dimer-DNA Complex

Ferric uptake regulation protein is a repressor protein which binds an AT rich region of DNA (the iron box). Fur binds as a dimer in a helix turn helix mode and it is activated by iron(II) and other transition metal ions at elevated concentrations. Each transition metal ion induces certain conformational changes to aid the Fur binding, both the N-terminal and C-terminal domains take part in binding to DNA in addition to His 88 and His 86. The process is discussed in view of experimental reports. Fe(II), Mn(II) and Co(II) activate Fur to bind DNA but Zinc plays a structural role and does not activate Fur to bind DNA.

The Role of Divalent Transition Metal Ions in the Binding of Fur Dimer to DNA: Binding of Mn2+ and Co2+ to EC Fur dimer-DNA Complex

Ferric uptake regulation protein is a repressor protein which binds an AT rich region of DNA (the iron box). Fur binds as a dimer in a helix turn helix mode and it is activated by iron(II) and other transition metal ions at elevated concentrations. Each transition metal ion induces certain conformational changes to aid the Fur binding, both the N-terminal and C-terminal domains take part in binding to DNA in addition to His 88 and His 86. The process is discussed in view of experimental reports. Fe(II), Mn(II) and Co(II) activate Fur to bind DNA but Zinc plays a structural role and does not activate Fur to bind DNA.