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The placenta is vital for supporting embryonic development and ensuring a successful pregnancy. Its diverse functions are carried out by specialized trophoblast cell types, including the progenitor cytotrophoblast, the multinucleated syncytiotrophoblast, and the invasive extravillous trophoblast. The distinct identities of these cells are governed by tightly regulated gene expression programs, controlled by transcription factors and cis-regulatory elements, particularly enhancers and silencers. They integrate spatiotemporal cues to modulate transcriptional activity and establish cell-type-specific gene expression profiles. Disruptions of these regulatory mechanisms can impair placental development and function, contributing to pregnancy complications. In this review, we explore the interplay between TFs and CREs in trophoblast lineage specification and function, with a focus on enhancers and silencers. We provide an overview of human placental development, describe commonly used in vitro models, and discuss recent technological advances that have deepened our understanding of transcriptional regulation in the placenta.

Repression of retrotransposition is crucial for the successful fitness of a mammalian organism. The domesticated transposon protein L1TD1, derived from LINE-1 (L1) ORF1p, is an RNA-binding protein that is expressed only in some cancers and early embryogenesis. In human embryonic stem cells, it is found to be essential for maintaining pluripotency. In cancer, L1TD1 expression is highly correlative with malignancy progression and as such considered a potential prognostic factor for tumors. However, its molecular role in cancer remains largely unknown. Our findings reveal that DNA hypomethylation induces the expression of L1TD1 in HAP1 human tumor cells. L1TD1 depletion significantly modulates both the proteome and transcriptome and thereby reduces cell viability. Notably, L1TD1 associates with L1 transcripts and interacts with L1 ORF1p protein, thereby facilitating L1 retrotransposition. Our data suggest that L1TD1 collaborates with its ancestral L1 ORF1p as an RNA chaperone, ensuring the efficient retrotransposition of L1 retrotransposons, rather than directly impacting the abundance of L1TD1 targets. In this way, L1TD1 might have an important role not only during early development but also in tumorigenesis.

Repression of retrotransposition is crucial for the successful fitness of a mammalian organism. The domesticated transposon protein L1TD1, derived from LINE-1 (L1) ORF1p, is an RNA-binding protein that is expressed only in some cancers and early embryogenesis. In human embryonic stem cells, it is found to be essential for maintaining pluripotency. In cancer, L1TD1 expression is highly correlative with malignancy progression and as such considered a potential prognostic factor for tumors. However, its molecular role in cancer remains largely unknown. Our findings reveal that DNA hypomethylation induces the expression of L1TD1 in HAP1 human tumor cells. L1TD1 depletion significantly modulates both the proteome and transcriptome and thereby reduces cell viability. Notably, L1TD1 associates with L1 transcripts and interacts with L1 ORF1p protein, thereby facilitating L1 retrotransposition. Our data suggest that L1TD1 collaborates with its ancestral L1 ORF1p as an RNA chaperone, ensuring the efficient retrotransposition of L1 retrotransposons, rather than directly impacting the abundance of L1TD1 targets. In this way, L1TD1 might have an important role not only during early development but also in tumorigenesis.

The class I histone deacetylases are essential regulators of cell fate decisions in health and disease. While pan- and class-specific HDAC inhibitors are available, these drugs do not allow a comprehensive understanding of individual HDAC function, or the therapeutic potential of isoform-specific targeting. To systematically compare the impact of individual catalytic functions of HDAC1, HDAC2 and HDAC3, we generated human HAP1 cell lines expressing catalytically inactive HDAC enzymes. Using this genetic toolbox we compare the effect of individual HDAC inhibition with the effects of class I specific inhibitors on cell viability, protein acetylation and gene expression. Individual inactivation of HDAC1 or HDAC2 has only mild effects on cell viability, while HDAC3 inactivation or loss results in DNA damage and apoptosis. Inactivation of HDAC1/HDAC2 led to increased acetylation of components of the COREST co-repressor complex, reduced deacetylase activity associated with this complex and derepression of neuronal genes. HDAC3 controls the acetylation of nuclear hormone receptor associated proteins and the expression of nuclear hormone receptor regulated genes. Acetylation of specific histone acetyltransferases and HDACs is sensitive to inactivation of HDAC1/HDAC2. Over a wide range of assays, we determined that in particular HDAC1 or HDAC2 catalytic inactivation mimics class I specific HDAC inhibitors. Importantly, we further demonstrate that catalytic inactivation of HDAC1 or HDAC2 sensitizes cells to specific cancer drugs. In summary, our systematic study revealed isoform-specific roles of HDAC1/2/3 catalytic functions. We suggest that targeted genetic inactivation of particular isoforms effectively mimics pharmacological HDAC inhibition allowing the identification of relevant HDACs as targets for therapeutic intervention.

Post-translational modifications of histones are important regulators of the DNA damage response (DDR). By using affinity purification mass spectrometry (AP-MS) we discovered that genetic suppressor element 1 (GSE1) forms a complex with the HDAC1/CoREST deacetylase/demethylase co-repressor complex. In-depth phosphorylome analysis revealed that loss of GSE1 results in impaired DDR, ATR signalling and γH2AX formation upon DNA damage induction. Altered profiles of ATR target serine-glutamine motifs (SQ) on DDR-related hallmark proteins point to a defect in DNA damage sensing. In addition, GSE1 knock-out cells showed hampered DNA damage-induced phosphorylation on SQ motifs of regulators of histone post-translational modifications, suggesting altered histone modification. While loss of GSE1 does not affect the histone deacetylation activity of CoREST, GSE1 appears to be essential for binding of the deubiquitinase USP22 to CoREST and for the deubiquitination of H2B K120 in response to DNA damage. The combination of deacetylase, demethylase, and deubiquitinase activity makes the USP22-GSE1-CoREST subcomplex a multi enzymatic eraser that seems to play an important role during DDR. Since GSE1 has been previously associated with cancer progression and survival our findings are potentially of high medical relevance.

Repression of retrotransposition is crucial for the successful fitness of a mammalian organism. The domesticated transposon protein L1TD1, derived from LINE-1 ORF1p, is an RNA-binding protein that is expressed only in some cancers and early embryogenesis. In human embryonic stem cells it is found to be essential for maintaining pluripotency. In cancer, L1TD1 expression is highly correlative with malignancy progression and as such considered a potential prognostic factor for tumors. However, its molecular role in cancer remains largely unknown. Our findings reveal that DNA hypomethylation induces the expression of L1TD1 in HAP1 human tumor cells. L1TD1 depletion significantly modulates both the proteome and transcriptome and thereby reduces cell viability. Notably, L1TD1 associates with LINE-1 transcripts and interacts with LINE-1 ORF1p protein, thereby facilitating LINE-1 retrotransposition. Our data suggest that L1TD1 collaborates with its ancestral LINE-1 ORF1p as an RNA chaperone, ensuring the efficient retrotransposition of LINE-1 retrotransposons, rather than directly impacting the abundance of L1TD1 targets. In this way, L1TD1 might have an important role not only during early development but also in tumorigenesis.Competing Interest StatementThe authors have declared no competing interest.Footnotes* We have discussed in more detail our model shown in Figure S7C. We have changed Figure 3E. We have deleted the paragraph discussing a direct relationship of our findings to embryology in the Discussion.

Histone deacetylases are key epigenetic regulators that control T cell-mediated immunity. A T cell-specific deletion of Hdac1 (HDAC1cKO) protects mice against experimental autoimmune encephalomyelitis (EAE). However, it remains elusive whether inhibition of HDAC1 enzymatic activity, which could be achieved therapeutically by HDAC1 inhibitor treatment, is sufficient to block EAE induction. In order to address this question, we generated a novel mouse strain that expresses catalytically inactive HDAC1 (HDAC1Off) from the Rosa26 locus in HDAC1cKO CD4+ T cells to mimic selective inhibition of HDAC1 enzymatic activity in vivo. Mice expressing wildtype HDAC1 in HDAC1cKO CD4+ T cells (HDAC1On) were generated as corresponding controls. In contrast to HDAC1On mice, HDAC1Off mice did not develop EAE, and this correlated with diminished leukocyte CNS infiltration. HDAC1Off CD4+ T cells in the CNS displayed a severe reduction of IFNγ, IL-17A and TNFα proinflammatory cytokine expression, and in vivo activated HDAC1Off CD4+ T cells downregulated gene sets associated with T cell activation, cytokine expression and cell migration. This indicates impaired effector functions of HDAC1Off CD4+ T cells. Taken together, our study demonstrates that the inhibition of the catalytic activity of HDAC1 in T cells is sufficient to achieve a clinical benefit in EAE disease development. This raises the translational perspective of pharmacological HDAC1 inhibition for treating human T cell-mediated autoimmune diseases. Successful generation of a novel mouse model that expresses enzymatic-inactive HDAC1 to mimic HDAC1 inhibitor treatment in vivo. Mice expressing enzymatically inactive HDAC1 instead of WT HDAC1 in T cells do not develop EAE and display diminished leukocyte CNS infiltration. In vivo activated CD4+ T cells expressing enzymatic inactive HDAC1 downregulate pathways important for T cell activation, cytokine expression and cell migration. Demonstrate the proof-of-principle that targeting the enzymatic activity of HDAC1 is a promising treatment strategy for autoimmune diseases.