## 1 Introduction  
Super-enhancers (SEs) are large genomic domains composed of multiple enhancer elements that facilitate high levels of gene expression [1, 2, 3, 4, 5]. SEs are characterized by dense clusters of transcription factors (TFs), chromatin regulators, such as H3K27 ac and BRD4, and coactivator complexes, such as Mediator [4, 5, 6, 7, 8, 9, 10]. They are pivotal in regulating cell identity, lineage commitment, and pathways implicated in various diseases [11, 12, 13, 14, 15, 16]. For example, in cancer, aberrant SE activity promotes oncogenesis by driving oncogene expression and supporting non-coding RNA transcription [17, 18, 19, 20, 21]. Unlike standard enhancers, SEs integrate multiple signals to sustain robust transcription, exhibiting dynamic states--conserved, temporally hierarchical, or de novo--during development and differentiation [22]. Although chromatin accessibility, TF-binding peaks, and histone modifications are central to defining SEs, these markers often show heterogeneous patterns [10; 23; 24]. Secondary DNA structures may play a role in further stratifying SE function, adding an additional layer of regulatory specificity [25; 26; 27]. One such secondary DNA structure attracting considerable attention is Z-DNA, a left-handed helical form stabilized by particular sequence motifs and torsional strain that has garnered increasing interest for its potential role in transcriptional regulation [28; 29; 30; 31]. Z-DNA often arises in actively transcribed regions due to negative supercoiling generated by RNA polymerase, with its formation relying on alternating syn- and anti-conformations in guanine and cytosine residues, where CpG dinucleotides adopt a characteristic \"Z-step\" conformation [30; 32]. Although Z-DNA has been associated with transcriptional activation by promoting nucleosome displacement or chromatin opening at promoters, its genome-wide distribution and functional significance in complex regulatory domains such as SEs remain insufficiently explored. It is well-established that Z-DNA can form chromosomal 'protrusions,' rendering Z-DNA-containing regions potential scaffolds for transcription factor (TF) binding [33]. Furthermore, the investigation revealed that predicted Z-DNA-forming sequences harbor binding motifs for zinc-finger family transcription factors. Given both the steric accessibility of Z-DNA-bearing regions and the identified TF binding sites, it is proposed that Z-DNA may employ a dual mechanism in transcriptional gene regulation. Z-DNA likely influences enhancer and super-enhancer activity by recruiting epigenetic modifiers that modulate various histone marks or DNA methylation profiles. Another possible Z-DNA function could be defined through Z-DNA as a structural determinant for long-range interactions through CTCF/cohesin-dependent mechanisms of action. Also, Z-DNA, due to its structural rigidity, may sustain torsional stress and therefore facilitate phase separation during looping and form the basis of essential SE-promotor insulation. Therefore, the suggested roles of Z-DNA may explain the observed enrichment of its structures within the described super-enhancers. It should be noted that future work is needed in order to test these models using epigenomic and 3D genome mapping approaches. Given that SEs span tens of kilobases and contain numerous high-density TF-binding sites, localized shifts to Z-DNA could plausibly impact chromatin accessibility, TF recruitment, or enhancer-promoter communication. Z-DNA-forming sequences also frequently coincide with promoter sites for the nuclear factor I (NFI) family, reinforcing the idea that these secondary structures have a functional impact on transcriptional dynamics [34]. Moreover, Z-DNA formation has been implicated in oncogene regulation (e.g., _c-MYC_ and _ADAM12_) and genomic instability, further linking it to the dysregulation observed in cancer [35; 36; 37; 38; 39]. In addition to SEs and Z-DNA, various feedback loops can also modulate transcription levels, ultimately influencing cell fate decisions.